82 results on '"Bates, Susan"'
Search Results
2. A Phase I Study of a Combination of Liposomal Irinotecan and Veliparib in Solid Tumors.
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LaRose M, Connolly RM, O'Sullivan CC, Velcheti V, Vilimas R, Gano K, Bates SE, Pommier Y, and Thomas A
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- Humans, Irinotecan pharmacology, Irinotecan therapeutic use, Poly(ADP-ribose) Polymerase Inhibitors adverse effects, Topoisomerase I Inhibitors adverse effects, Poly(ADP-ribose) Polymerases, Diarrhea chemically induced, Antineoplastic Combined Chemotherapy Protocols adverse effects, Neoplasms drug therapy, Neoplasms pathology, Antineoplastic Agents therapeutic use
- Abstract
Background: Multiple preclinical studies have shown cytotoxic synergy involving combinations of poly (ADP-ribose) polymerase (PARP) inhibitors and topoisomerase 1 (TOP1) inhibitors, but such combinations have proven too toxic in clinical trials. Liposomal irinotecan (nal-IRI) achieved similar intratumoral exposure with better antitumor activity than the conventional TOP1 inhibitor irinotecan in preclinical models. Tumor targeted delivery of TOP1 inhibitor using nal-IRI and an intermittent schedule of administration of PARP inhibitor may provide a tolerable combination., Methods: A phase I study was performed to evaluate the safety and tolerability of escalating doses of nal-IRI and the PARP inhibitor veliparib in patients with solid tumors resistant to standard treatments. Nal-IRI was administered on days 1 and 15 and veliparib on days 5-12 and 19-25 in 28-day cycles., Results: Eighteen patients were enrolled across 3 dose levels. Five patients encountered dose-limiting toxicities, including grade 3 diarrhea lasting more than 72 h in 3 patients and 1 patient each with grade 4 diarrhea and grade 3 hyponatremia. The most common grade 3 or 4 toxicities included diarrhea (50% of patients), nausea (16.6%), anorexia, and vomiting (11.1% each) (Table 1). There was no difference in frequencies of adverse events based on UGT1A1*28 status or prior opioid use (Table 1)., Conclusion: The clinical trial was terminated due to high frequency of unacceptable gastrointestinal toxicities, which precluded dose escalation of veliparib in combination with nal-IRI (ClinicalTrials.gov Identifier: NCT02631733)., (Published by Oxford University Press 2023.)
- Published
- 2023
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3. Targeting Translation of mRNA as a Therapeutic Strategy in Cancer.
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Pal I, Safari M, Jovanovic M, Bates SE, and Deng C
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- Animals, Biomarkers, Gene Expression Regulation, Neoplastic drug effects, Humans, Neoplasms metabolism, Signal Transduction drug effects, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Molecular Targeted Therapy, Neoplasms drug therapy, Neoplasms genetics, Protein Biosynthesis drug effects, RNA, Messenger genetics
- Abstract
Purpose of Review: To highlight recent results in targeting mRNA translation and discuss the results and prospects of translation inhibitors in cancer therapy., Recent Findings: Until recently, inhibitors of mRNA translation have been thought to likely lack a therapeutic window. In 2012, the Food and Drug Administration (FDA) approved omacetaxine mepesuccinate (homoharringtonine) for the treatment of adults with chronic myelogenous leukemia (CML) who are resistant to at least two tyrosine kinase inhibitors. Since then, a few drugs, notably tomivosertib (eFT-508), selinexor (KPT-330), and ribavirin, have entered clinical trials. These drugs are known to inhibit mRNA translation. More recently, a number of interesting studies report that discrete subsets of proteins in cancer cells may be selectively targeted at the translation step, through inhibiting signals such as phospho-4E-BP1, eIF4A, and eIF4E. Promising therapies using these strategies have demonstrated potent anti-tumor activity in preclinical cancer models. The growing number of translation inhibitors with diverse mechanisms, coupled with emerging insights into translational regulation of different cancer-promoting genes, suggests a bright new horizon for the field of therapeutic targeting of mRNA translation in cancer.
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- 2019
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4. Cisplatin Every 3 Weeks Versus Weekly With Definitive Concurrent Radiotherapy for Squamous Cell Carcinoma of the Head and Neck.
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Bauml JM, Vinnakota R, Anna Park YH, Bates SE, Fojo T, Aggarwal C, Limaye S, Damjanov N, Di Stefano J, Ciunci C, Genden EM, Wisnivesky JP, Ferrandino R, Mamtani R, Langer CJ, Cohen RB, and Sigel K
- Subjects
- Acute Kidney Injury chemically induced, Aged, Antineoplastic Agents adverse effects, Chemoradiotherapy adverse effects, Confidence Intervals, Drug Administration Schedule, Female, Head and Neck Neoplasms mortality, Head and Neck Neoplasms pathology, Humans, Intention to Treat Analysis, Male, Middle Aged, Propensity Score, Radiation-Sensitizing Agents adverse effects, Squamous Cell Carcinoma of Head and Neck mortality, Squamous Cell Carcinoma of Head and Neck pathology, Treatment Outcome, Veterans, Antineoplastic Agents administration & dosage, Chemoradiotherapy methods, Cisplatin administration & dosage, Head and Neck Neoplasms therapy, Radiation-Sensitizing Agents administration & dosage, Squamous Cell Carcinoma of Head and Neck therapy
- Abstract
Background: Concurrent chemoradiotherapy is an established component of the nonoperative management of locally advanced head and neck squamous cell carcinoma (HNSCC), but the standard dose of 100 mg/m2 cisplatin every 3 weeks is associated with clinically significant toxicity. Interest in a more tolerable regimen has led to the widespread use of weekly lower dose cisplatin, but few randomized trials have compared these approaches., Methods: We examined outcomes of patients with stage III-IVb HNSCC treated with definitive intent chemoradiotherapy using either high-dose cisplatin (HDC) or low-dose cisplatin (LDC), using population-based Veterans Affairs data. In an intent-to-treat analysis, patients were assigned to the HDC vs LDC group according to the dose of their first cycle. Variables potentially influencing treatment decisions including cancer site, stage, smoking/alcohol use, and comorbidities were used to generate propensity scores (PS) for the use of HDC. We compared overall survival (OS) by treatment group using Cox regression, adjusting for PS. We then determined the risk of toxicities using PS-adjusted logistic regression., Results: A total of 2901 patients were included in the analysis; 2200 received HDC (mean initial dose 100 mg/m2). The mean initial dose of LDC was 40 mg/m2. After PS adjustment, HDC was not associated with improved OS over LDC (hazard ratio = 0.94, 95% confidence interval = 0.80 to 1.04). Adjusting for PS, HDC was associated with an increased risk of acute kidney injury, neutropenia, dehydration/electrolyte disturbance, and hearing loss., Conclusion: In this large, population-based study of US military veterans, LDC was associated with similar survival to HDC in the nonoperative definitive management of locally advanced HNSCC of the oral cavity, oropharynx, and hypopharynx/larynx. HDC was associated with statistically significantly more toxicity than LDC. Adoption of LDC may reduce toxicity burden while maintaining OS., (Published by Oxford University Press 2018.)
- Published
- 2019
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5. Targeting mitochondrial hexokinases increases efficacy of histone deacetylase inhibitors in solid tumor models.
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McDonald AJ, Curt KM, Patel RP, Kozlowski H, Sackett DL, Robey RW, Gottesman MM, and Bates SE
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- A549 Cells, Clotrimazole pharmacology, Depsipeptides pharmacology, Drug Synergism, HCT116 Cells, Humans, Imidazoles pharmacology, Mitochondria drug effects, Protein Transport drug effects, Antineoplastic Agents pharmacology, Apoptosis drug effects, Hexokinase metabolism, Histone Deacetylases pharmacology, Neoplasms metabolism
- Abstract
Hexokinase 1 and 2 have been shown to inhibit Bak- and Bax-mediated apoptosis, leading us to combine the histone deacetylase inhibitor romidepsin with clotrimazole or bifonazole, two compounds that reportedly decrease mitochondrial localization of hexokinases. Cancer cell lines derived from breast, kidney, lung, colon or ovarian cancers were treated with a short-term exposure to 25 ng/ml romidepsin combined with either clotrimazole or bifonazole. The combination of romidepsin with 25 µM clotrimazole or bifonazole resulted in increased annexin staining compared to cells treated with any of the drugs alone. Cell death was caspase-mediated, as the pan-caspase inhibitor Q-VD-OPh was found to inhibit apoptosis induced by the combination. A549 lung cancer cells or HCT-116 cells deficient in Bak and Bax were also resistant to apoptosis with the combination implicating the intrinsic apoptotic pathway. We found that a 24 h treatment with clotrimazole or bifonazole decreased total hexokinase 2 expression, resulting in a 76% or 60% decrease, respectively, of mitochondrial expression of hexokinase 2. Mitochondrial hexokinase 1 levels increased 2-fold or less. Our work suggests that the combination of a short-term romidepsin treatment with bifonazole or clotrimazole leads to increased apoptosis, most likely due to decreased mitochondrial expression of hexokinase 2., (Copyright © 2018. Published by Elsevier Inc.)
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- 2019
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6. Current challenges in the management of breast cancer brain metastases.
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O'Sullivan CC, Davarpanah NN, Abraham J, and Bates SE
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- Blood-Brain Barrier, Brain Neoplasms diagnostic imaging, Brain Neoplasms secondary, Breast Neoplasms chemistry, Female, Humans, Meningeal Neoplasms secondary, Neovascularization, Pathologic drug therapy, Receptor, ErbB-2 analysis, Receptors, Estrogen analysis, Antineoplastic Agents therapeutic use, Brain Neoplasms drug therapy, Breast Neoplasms pathology, Meningeal Neoplasms drug therapy, Receptor, ErbB-2 drug effects
- Abstract
Approximately 50% of patients with advanced human epidermal growth factor 2 (HER2)-positive breast cancer and triple-negative breast cancer (TNBC) ultimately develop breast cancer brain metastases (BCBM), which are associated with significant morbidity and mortality. The advent of HER2-directed therapy resulted in greatly improved survival outcomes, but unfortunately at the price of an increased cumulative incidence of BCBM. We review challenges in the management of BCBM, and potential treatment strategies, including novel agents such as poly-adenosine diphosphate (ADP) ribose polymerase (PARP) inhibitors (olaparib, veliparib), cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (palbociclib, abemaciclib), and taxane derivatives (eg, ANG1005 and TPI-287). The utility of human epidermal growth factor 2 (HER2)-directed therapies-lapatinib, ado-trastuzumab emtansine (T-DM1), neratinib and tucatinib-is also being studied in this setting. We address the need for improved imaging techniques and innovation in clinical trial design. For example, the current practice is to initially administer whole-brain radiotherapy (WBRT) as treatment for patients with multiple BCBM. However, in selected circumstances, first-line systemic treatment may be more appropriate in order to avoid neurocognitive toxicities, and potential options should be evaluated in window of opportunity trials. Other strategies that may aid development of more effective clinical trials and expedite the development of promising agents include the use of different clinical endpoints and different imaging tools., (Copyright © 2017 Elsevier Inc. All rights reserved.)
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- 2017
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7. Multiple Myeloma: Multiplying Therapies.
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Bates SE
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- Humans, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Multiple Myeloma drug therapy
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- 2016
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8. Disruptive Immunology.
- Author
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Bates SE
- Subjects
- Antineoplastic Agents pharmacology, Humans, Immunotherapy, Antineoplastic Agents therapeutic use, Immunomodulation drug effects, Neoplasms immunology, Neoplasms therapy
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- 2016
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9. UGT1A1 genotype-dependent dose adjustment of belinostat in patients with advanced cancers using population pharmacokinetic modeling and simulation.
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Peer CJ, Goey AK, Sissung TM, Erlich S, Lee MJ, Tomita Y, Trepel JB, Piekarz R, Balasubramaniam S, Bates SE, and Figg WD
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- Adult, Aged, Albumins metabolism, Creatinine metabolism, Female, Genotype, Humans, Kinetics, Male, Middle Aged, Models, Biological, Neoplasms genetics, Neoplasms metabolism, Pharmacogenetics methods, Antineoplastic Agents administration & dosage, Antineoplastic Agents pharmacokinetics, Glucuronosyltransferase genetics, Hydroxamic Acids administration & dosage, Hydroxamic Acids pharmacokinetics, Neoplasms drug therapy, Sulfonamides administration & dosage, Sulfonamides pharmacokinetics
- Abstract
Belinostat is a second-generation zinc-binding histone deacetylase inhibitor that is approved for peripheral T-cell lymphoma and is currently being studied in small cell lung cancer and other advanced carcinomas as a 48-hour continuous intravenous infusion. Belinostat is predominantly metabolized by UGT1A1, which is polymorphic. Preliminary analyses revealed a difference in belinostat clearance based on UGT1A1 genotype. A 2-compartment population pharmacokinetic (PK) model was developed and validated that incorporated the UGT1A1 genotype, albumin, and creatinine clearance on the clearance parameter; body weight was a significant covariate on volume. Simulated doses of 600 and 400 mg/m(2) /24 h given to patients considered extensive or impaired metabolizers, respectively, provided equivalent AUCs. This model and subsequent simulations supported additional PK/toxicity and pharmacogenomics/toxicity analyses to suggest a UGT1A1 genotype-based dose adjustment to normalize belinostat exposure and allow for more tolerable therapy. In addition, global protein lysine acetylation was modeled with PK and demonstrated a reversible belinostat exposure/response relationship, consistent with previous reports., (© 2015, The American College of Clinical Pharmacology.)
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- 2016
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10. On Innovating and Inspiring the Clinical Trial Enterprise.
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Bates SE
- Subjects
- Clinical Trials as Topic, Humans, Medical Oncology methods, Antineoplastic Agents therapeutic use, Neoplasms drug therapy
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- 2015
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11. Advancing Clinical Trials to Streamline Drug Development.
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Bates SE, Berry DA, Balasubramaniam S, Bailey S, LoRusso PM, and Rubin EH
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- Animals, Clinical Trials as Topic, Drug Approval methods, Drug Discovery methods, Genomics, Humans, Neoplasms genetics, Research Personnel, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Neoplasms drug therapy
- Abstract
The last decade in oncology has been marked by the identification of numerous new potential cancer targets and even more agents designed to inhibit them. The matrix of new targets, new agents, and the companion diagnostics required to identify the right patient for the right drug has created a major challenge for the clinical trial process. This has been compounded by the addition of new immunomodulators targeting the host immune system rather than the tumor. Recognizing the need for new approaches, industry, investigators, and regulators have responded to this challenge. New clinical trial designs are being evaluated to incorporate the genomic sequence data being obtained almost routinely after cancer diagnosis. New dose-finding approaches are being proposed to identify the maximum effective dose rather than the maximum tolerated dose. The FDA is involved in the drug approval process from points early in development and has accepted registration quality data from expansion cohorts in support of drug approval. Despite progress on several fronts, many challenges remain, including the lack of predictability of preclinical data for clinical results and phase II data for phase III results, an infrastructure that can be an obstacle to clinical trial development and implementation, and the increasing use of contracted clinical research organizations that limit a fit-for-purpose approach to clinical trial execution. Perhaps most challenging and important of all are the difficulties with clinical trial accrual that can prevent study completion. Both the innovations and the challenges highlight the important role of process in progress in clinical oncology., (©2015 American Association for Cancer Research.)
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- 2015
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12. A phase i study of DMS612, a novel bifunctional alkylating agent.
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Appleman LJ, Balasubramaniam S, Parise RA, Bryla C, Redon CE, Nakamura AJ, Bonner WM, Wright JJ, Piekarz R, Kohler DR, Jiang Y, Belani CP, Eiseman J, Chu E, Beumer JH, and Bates SE
- Subjects
- Adult, Aged, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacokinetics, Benzaldehydes adverse effects, Benzaldehydes pharmacokinetics, Dose-Response Relationship, Drug, Female, Humans, Male, Maximum Tolerated Dose, Middle Aged, Antineoplastic Agents administration & dosage, Benzaldehydes administration & dosage, Neoplasms drug therapy
- Abstract
Purpose: DMS612 is a dimethane sulfonate analog with bifunctional alkylating activity and preferential cytotoxicity to human renal cell carcinoma (RCC) in the NCI-60 cell panel. This first-in-human phase I study aimed to determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of DMS612 administered by 10-minute intravenous infusion on days 1, 8, and 15 of an every-28-day schedule., Experimental Design: Patients with advanced solid malignancies were eligible. Enrollment followed a 3+3 design. PKs of DMS612 and metabolites were assessed by mass spectroscopy and PD by γ-H2AX immunofluorescence., Results: A total of 31 patients, including those with colorectal (11), RCC (4), cervical (2), and urothelial (1) cancers, were enrolled. Six dose levels were studied, from 1.5 mg/m(2) to 12 mg/m(2). DLTs of grade 4 neutropenia and prolonged grade 3 thrombocytopenia were observed at 12 mg/m(2). The MTD was determined to be 9 mg/m(2) with a single DLT of grade 4 thrombocytopenia in 1 of 12 patients. Two patients had a confirmed partial response at the 9 mg/m(2) dose level, in renal (1) and cervical (1) cancer. DMS612 was rapidly converted into active metabolites. γ-H2AX immunofluorescence revealed dose-dependent DNA damage in both peripheral blood lymphocytes and scalp hairs., Conclusions: The MTD of DMS12 on days 1, 8, and 15 every 28 days was 9 mg/m(2). DMS612 appears to be an alkylating agent with unique tissue specificities. Dose-dependent PD signals and two partial responses at the MTD support further evaluation of DMS612 in phase II trials., (©2014 American Association for Cancer Research.)
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- 2015
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13. The lymphoma medicine cabinet.
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Bates SE
- Subjects
- Humans, Lymphoma etiology, Antineoplastic Agents therapeutic use, Lymphoma drug therapy
- Published
- 2014
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14. Therapies with diverse mechanisms of action kill cells by a similar exponential process in advanced cancers.
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Blagoev KB, Wilkerson J, Stein WD, Yang J, Bates SE, and Fojo T
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- Animals, Humans, Kinetics, Models, Biological, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Cell Death drug effects, Cell Death physiology, Neoplasms drug therapy, Neoplasms pathology
- Abstract
Successful cancer treatments are generally defined as those that decrease tumor quantity. In many cases, this decrease occurs exponentially, with deviations from a strict exponential being attributed to a growing fraction of drug-resistant cells. Deviations from an exponential decrease in tumor quantity can also be expected if drugs have a nonuniform spatial distribution inside the tumor, for example, because of interstitial pressure inside the tumor. Here, we examine theoretically different models of cell killing and analyze data from clinical trials based on these models. We show that the best description of clinical outcomes is by first-order kinetics with exponential decrease of tumor quantity. We analyzed the total tumor quantity in a diverse group of clinical trials with various cancers during the administration of different classes of anticancer agents and in all cases observed that the models that best fit the data describe the decrease of the sensitive tumor fraction exponentially. The exponential decrease suggests that all drug-sensitive cancer cells have a single rate-limiting step on the path to cell death. If there are intermediate steps in the path to cell death, they are not rate limiting in the observational time scale utilized in clinical trials--tumor restaging at 6- to 8-week intervals. On shorter time scales, there might be intermediate steps, but the rate-limiting step is the same. Our analysis, thus, points to a common pathway to cell death for cancer cells in patients. See all articles in this Cancer Research section, "Physics in Cancer Research.", (©2014 American Association for Cancer Research.)
- Published
- 2014
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15. The language of pharmacodynamics.
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Bates SE
- Subjects
- Animals, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacokinetics, Drug-Related Side Effects and Adverse Reactions etiology, Humans, Models, Biological, Neoplasms metabolism, Treatment Outcome, Antineoplastic Agents pharmacology, Neoplasms drug therapy
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- 2014
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16. Continuing a cancer treatment despite tumor growth may be valuable: sunitinib in renal cell carcinoma as example.
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Burotto M, Wilkerson J, Stein W, Motzer R, Bates S, and Fojo T
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- Angiogenesis Inhibitors administration & dosage, Angiogenesis Inhibitors adverse effects, Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Cell Proliferation drug effects, Disease-Free Survival, Humans, Indoles administration & dosage, Indoles adverse effects, Kidney Neoplasms, Pyrroles administration & dosage, Pyrroles adverse effects, Sunitinib, Treatment Outcome, Angiogenesis Inhibitors therapeutic use, Antineoplastic Agents therapeutic use, Carcinoma, Renal Cell drug therapy, Indoles therapeutic use, Pyrroles therapeutic use
- Abstract
Background: The US FDA and the EMA have approved seven agents for the treatment of renal cell carcinoma, primarily based on differences in progression-free survival (PFS). Because PFS is an arbitrary endpoint we hypothesized that an analysis would demonstrate the growth rate of tumors remained constant at the time of RECIST-defined disease progression., Methods: We previously estimated the growth (g) and regression (d) rates and the stability of g using data from the Phase III trial comparing sunitinib and interferon., Results: Sufficient data were available and rate constants statistically valid in 321 of 374 patients randomized to sunitinib. Median d was 0•0052 days(-1); in 53 patients no tumor growth was recorded. Median g was 0•00082 days(-1) and was stable for a median of 275 days on therapy, remaining stable beyond 300, 600 and 900 days in 122, 65 and 27 patients, respectively. A possible increase in g while receiving sunitinib could be discerned in only 18 of 321 patients. Given a median g of 0•00082 days(-1) the estimated median time to a second progression were sunitinib continued past RECIST-defined progression was 7.3 months. At 100, 200, and 300 days after starting therapy, an estimated 47%, 27%, and 13% of tumor remains sunitinib sensitive and could explain a RECIST-defined response to a new TKI., Conclusion: Prolonged stability of g with sunitinib suggests continued sunitinib beyond RECIST-defined progression may provide a beneficial outcome. Randomized trials in patients whose disease has "progressed" on sunitinib are needed to test this hypothesis.
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- 2014
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17. Waking the immune system at last.
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Bates SE
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- Animals, Humans, Neoplasms therapy, Antineoplastic Agents therapeutic use, Immune System drug effects, Immunologic Factors therapeutic use, Neoplasms immunology
- Published
- 2013
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18. Sunitinib does not accelerate tumor growth in patients with metastatic renal cell carcinoma.
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Blagoev KB, Wilkerson J, Stein WD, Motzer RJ, Bates SE, and Fojo AT
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- Carcinoma, Renal Cell mortality, Carcinoma, Renal Cell secondary, Cell Proliferation, Humans, Interferon-alpha therapeutic use, Kidney Neoplasms mortality, Kidney Neoplasms secondary, Sunitinib, Survival Analysis, Antineoplastic Agents therapeutic use, Carcinoma, Renal Cell drug therapy, Indoles therapeutic use, Kidney Neoplasms drug therapy, Pyrroles therapeutic use
- Abstract
Preclinical studies have suggested that sunitinib accelerates metastases in animals, ascribing this to inhibition of the vascular endothelial growth factor receptor or the tumor's adaptation. To address whether sunitinib accelerates tumors in humans, we analyzed data from the pivotal randomized phase III trial comparing sunitinib and interferon alfa in patients with metastatic renal cell carcinoma. The evidence clearly shows that sunitinib was not harmful, did not accelerate tumor growth, and did not shorten survival. Specifically, neither longer sunitinib treatment nor a greater effect of sunitinib on tumors reduced survival. Sunitinib did reduce the tumor's growth rate while administered, thereby improving survival, without appearing to alter tumor biology after discontinuation. Concerns arising from animal models do not apply to patients receiving sunitinib and likely will not apply to similar agents., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
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19. Mechanisms of resistance to PARP inhibitors--three and counting.
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Fojo T and Bates S
- Subjects
- Animals, Female, Tumor Suppressor p53-Binding Protein 1, Antineoplastic Agents therapeutic use, Chromosomal Proteins, Non-Histone genetics, DNA-Binding Proteins genetics, Drug Resistance, Neoplasm, Enzyme Inhibitors therapeutic use, Phthalazines therapeutic use, Piperazines therapeutic use, Poly(ADP-ribose) Polymerase Inhibitors
- Abstract
Given the malleable nature of cancer cells, we should expect, and do see, the development of resistance to any new chemotherapeutic agent. Models that help us understand how this happens are a first step to better and more effective chemotherapeutics.
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- 2013
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20. Analyzing the pivotal trial that compared sunitinib and IFN-α in renal cell carcinoma, using a method that assesses tumor regression and growth.
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Stein WD, Wilkerson J, Kim ST, Huang X, Motzer RJ, Fojo AT, and Bates SE
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- Carcinoma, Renal Cell pathology, Cell Proliferation drug effects, Disease-Free Survival, Humans, Kidney Neoplasms mortality, Kidney Neoplasms pathology, Remission Induction methods, Sunitinib, Survival Rate, Treatment Outcome, Antineoplastic Agents therapeutic use, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell mortality, Indoles therapeutic use, Interferon-alpha therapeutic use, Kidney Neoplasms drug therapy, Pyrroles therapeutic use
- Abstract
Purpose: We applied a method that analyzes tumor response, quantifying the rates of tumor growth (g) and regression (d), using tumor measurements obtained while patients receive therapy. We used data from the phase III trial comparing sunitinib and IFN-α in metastatic renal cell carcinoma (mRCC) patients., Methods: The analysis used an equation that extracts d and g., Results: For sunitinib, overall survival (OS) was strongly correlated with log g (Rsq = 0.44, P < 0.0001); much less with log d (Rsq = 0.04; P = 0.0002). The median g of tumors in these patients (0.00082 per days; log g = -3.09) was about half that (P < 0.001) of tumors in patients receiving IFN-α (0.0015 per day; log g = -2.81). With IFN-α, the OS/log g correlation (Rsq = 0.14) was weaker. Values of g from measurements obtained by study investigators or central review were highly correlated (Rsq = 0.80). No advantage resulted in including data from central review in regressions. Furthermore, g can be estimated accurately four months before treatment discontinuation. Extrapolating g in a model that incorporates survival generates the hypothesis that g increased after discontinuation of sunitinib but did not accelerate., Conclusions: In patients with mRCC, sunitinib reduced tumor growth rate, g, more than did IFN-α. Correlating g with OS confirms earlier analyses suggesting g may be an important clinical trial endpoint, to be explored prospectively and in individual patients., (©2012 AACR.)
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- 2012
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21. Romidepsin: a new drug for the treatment of cutaneous T-cell lymphoma.
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Frye R, Myers M, Axelrod KC, Ness EA, Piekarz RL, Bates SE, and Booher S
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- Animals, Antineoplastic Agents adverse effects, Clinical Trials as Topic, Depsipeptides adverse effects, Drug Approval, Histone Deacetylase Inhibitors therapeutic use, Humans, Lymphoma, T-Cell nursing, Recurrence, Skin Neoplasms nursing, Antineoplastic Agents therapeutic use, Depsipeptides therapeutic use, Lymphoma, T-Cell drug therapy, Skin Neoplasms drug therapy
- Abstract
Patients with cutaneous T-cell lymphoma (CTCL) have a rare, disfiguring, and life-threatening subtype of non-Hodgkin lymphoma primarily localized to the skin. Their immune systems are altered and their skin is compromised. In addition, they are highly prone to infections-the most common cause of death in patients with this disease. Patients presenting with early-stage disease involvement typically are treated with topical therapies; patients with advanced-stage and recurrent disease require systemic treatment. Specialized knowledge is required by oncology healthcare providers to manage the wide array of symptoms experienced by these patients as a part of the natural course of this disease. A new drug, romidepsin, approved by the U.S. Food and Drug Administration, is indicated in the treatment of relapsed CTCL. The authors discuss use of romidepsin in the context of CTCL and the information needed to safely administer romidepsin and manage its side effects.
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- 2012
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22. Drug resistance: still a daunting challenge to the successful treatment of AML.
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Shaffer BC, Gillet JP, Patel C, Baer MR, Bates SE, and Gottesman MM
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- ATP Binding Cassette Transporter, Subfamily B, ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Animals, Biological Transport drug effects, Clinical Trials as Topic, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic drug effects, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Mice, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Polymorphism, Single Nucleotide, Protein Isoforms antagonists & inhibitors, Protein Isoforms genetics, Protein Isoforms metabolism, ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors, Antineoplastic Agents therapeutic use, Drug Resistance, Neoplasm drug effects, Leukemia, Myeloid, Acute drug therapy
- Abstract
Resistance to chemotherapy remains a challenging issue for patients and their physicians. P-glycoprotein (Pgp, MDR1, ABCB1), as well as a family of structurally and functionally related proteins, are plasma membrane transporters able to efflux a variety of substrates from the cell cytoplasm, including chemotherapeutic agents. The discovery of ABCB1 made available a potential target for pharmacologic down-regulation of efflux-mediated chemotherapy resistance. In patients with acute myeloid leukemia (AML), a neoplasm characterized by proliferation of poorly differentiated myeloid progenitor cells, leukemic cells often express ABCB1 at high levels, which may lead to the development of resistance to chemotherapy. Thus, AML seemed to be a likely cancer for which the addition of drug efflux inhibitors to the chemotherapeutic regimen would improve outcomes in patients. Despite this rational hypothesis, the majority of clinical trials evaluating this strategy have failed to reach a positive endpoint, most recently the Eastern Cooperative Oncology Group E3999 trial. Here we review data suggesting the importance of ABCB1 in AML, address the failure of clinical trials to support a therapeutic strategy aimed at modulating ABCB1-mediated resistance, and consider the type of research that should be conducted in this field going forward., (Published by Elsevier Ltd.)
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- 2012
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23. Targeting MDR in breast and lung cancer: discriminating its potential importance from the failure of drug resistance reversal studies.
- Author
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Amiri-Kordestani L, Basseville A, Kurdziel K, Fojo AT, and Bates SE
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- ATP Binding Cassette Transporter, Subfamily B, ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Animals, Biological Transport drug effects, Breast Neoplasms genetics, Breast Neoplasms metabolism, Clinical Trials as Topic, Drug Resistance, Neoplasm drug effects, Female, Gene Expression Regulation, Neoplastic drug effects, Humans, Lung Neoplasms genetics, Lung Neoplasms metabolism, Mice, Treatment Outcome, ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors, Antineoplastic Agents therapeutic use, Breast Neoplasms drug therapy, Lung Neoplasms drug therapy, Molecular Targeted Therapy methods
- Abstract
This special issue of Drug Resistance Updates is dedicated to multidrug resistance protein 1 (MDR-1), 35 years after its discovery. While enormous progress has been made and our understanding of drug resistance has become more sophisticated and nuanced, after 35 years the role of MDR-1 in clinical oncology remains a work in progress. Despite clear in vitro evidence that P-glycoprotein (Pgp), encoded by MDR-1, is able to dramatically reduce drug concentrations in cultured cells, and that drug accumulation can be increased by small molecule inhibitors, clinical trials testing this paradigm have mostly failed. Some have argued that it is no longer worthy of study. However, repeated analyses have demonstrated MDR-1 expression in a tumor is a poor prognostic indicator leading some to conclude MDR-1 is a marker of a more aggressive phenotype, rather than a mechanism of drug resistance. In this review we will re-evaluate the MDR-1 story in light of our new understanding of molecular targeted therapy, using breast and lung cancer as examples. In the end we will reconcile the data available and the knowledge gained in support of a thesis that we understand far more than we realize, and that we can use this knowledge to improve future therapies., (Published by Elsevier Ltd.)
- Published
- 2012
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24. Drug development: portals of discovery.
- Author
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Bates SE, Amiri-Kordestani L, and Giaccone G
- Subjects
- Animals, Clinical Trials as Topic, Humans, Antineoplastic Agents therapeutic use, Drug Design, Neoplasms drug therapy, Research Design
- Abstract
A British humorist said, "There is much to be said for failure. It is much more interesting than success." This CCR Focus section is aimed at identifying lessons to be learned from difficulties encountered in recent years during development of anticancer agents. Clearly, we have not found a silver bullet tyrosine kinase inhibitor against solid tumors comparable with imatinib in chronic myelogenous leukemia. Although vemurafenib for B-Raf-mutated melanoma and crizotinib for non-small cell lung cancers with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements were developed rapidly and offer hope for individualized targeted therapies, the development of agents targeting a number of other pathways has been slower and less successful. These agents include drugs for blocking the insulin-like growth factor I/insulin receptor pathways, mitotic kinase inhibitors, and Hsp90 antagonists. Several potentially useful, if not groundbreaking, agents have had setbacks in clinical development, including trastuzumab emtansine, gemtuzumab ozogamicin, and satraplatin. From experience, we have learned the following: (i) not every altered protein or pathway is a valid anticancer target; (ii) drugs must effectively engage the target; (iii) the biology of the systems we use must be very well understood; and (iv) clinical trials must be designed to assess whether the drug reached and impaired the target. It is also important that we improve the drug development enterprise to enhance enrollment, streamline clinical trials, reduce financial risk, and encourage the development of agents for niche indications. Such enormous challenges are offset by potentially tremendous gains in our understanding and treatment of cancer., (© 2012 AACR.)
- Published
- 2012
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25. A pharmacodynamic study of the P-glycoprotein antagonist CBT-1® in combination with paclitaxel in solid tumors.
- Author
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Kelly RJ, Robey RW, Chen CC, Draper D, Luchenko V, Barnett D, Oldham RK, Caluag Z, Frye AR, Steinberg SM, Fojo T, and Bates SE
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Adult, Aged, Antineoplastic Agents pharmacology, Drug Interactions, Female, Humans, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear metabolism, Liver drug effects, Liver metabolism, Male, Middle Aged, Paclitaxel pharmacology, Radiopharmaceuticals pharmacokinetics, Rhodamine 123 pharmacokinetics, Technetium Tc 99m Sestamibi pharmacokinetics, ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors, Abdominal Neoplasms drug therapy, Abdominal Neoplasms metabolism, Alkaloids pharmacology, Antineoplastic Agents pharmacokinetics, Paclitaxel pharmacokinetics
- Abstract
Background: This pharmacodynamic trial evaluated the effect of CBT-1® on efflux by the ATP binding cassette (ABC) multidrug transporter P-glycoprotein (Pgp/MDR1/ABCB1) in normal human cells and tissues. CBT-1® is an orally administered bisbenzylisoquinoline Pgp inhibitor being evaluated clinically. Laboratory studies showed potent and durable inhibition of Pgp, and in phase I studies CBT-1® did not alter the pharmacokinetics of paclitaxel or doxorubicin., Methods: CBT-1® was dosed at 500 mg/m2 for 7 days; a 3-hour infusion of paclitaxel at 135 mg/m2 was administered on day 6. Peripheral blood mononuclear cells (PBMCs) were obtained prior to CBT-1® administration and on day 6 prior to the paclitaxel infusion. (99m)Tc-sestamibi imaging was performed on the same schedule. The area under the concentration-time curve from 0-3 hours (AUC(0-3)) was determined for (99m)Tc-sestamibi., Results: Twelve patients were planned and enrolled. Toxicities were minimal and related to paclitaxel (grade 3 or 4 neutropenia in 18% of cycles). Rhodamine efflux from CD56+ PBMCs was a statistically significant 51%-100% lower (p < .0001) with CBT-1®. Among 10 patients who completed imaging, the (99m)Tc-sestamibi AUC(0-3) for liver (normalized to the AUC(0-3) of the heart) increased from 34.7% to 100.8% (median, 71.9%; p < .0001) after CBT-1® administration. Lung uptake was not changed., Conclusion: CBT-1® is able to inhibit Pgp-mediated efflux from PBMCs and normal liver to a degree observed with Pgp inhibitors studied in earlier clinical trials. Combined with its ease of administration and lack of toxicity, the data showing inhibition of normal tissue Pgp support further studies with CBT-1® to evaluate its ability to modulate drug uptake in tumor tissue., Discussion: Although overexpression of ABCB1 and other ABC transporters has been linked with poor outcome following chemotherapy efforts to negate that through pharmacologic inhibition have generally failed. This is thought to be a result of several factors, including (a) failure to select patients with tumors in which ABCB1 is a dominant resistance mechanism; (b) inhibitors that were not potent, or that impaired drug clearance; and (c) the existence of other mechanisms of drug resistance, including other ABC transporters. Although an animal model for Pgp has been lacking, recent studies have exploited a Brca1(-/-); p53(-/-) mouse model of hereditary breast cancer that develops sporadic tumors similar to cancers in women harboring BRCA1 mutations. Treatment with doxorubicin, docetaxel, or the poly(ADP-ribose) polymerase inhibitor olaparib brings about shrinkage, but resistance eventually emerges. Overexpression of the Abcb1a gene, the mouse ortholog of human ABCB1, has been shown to be a mechanism of resistance in a subset of these tumors. Treating mice with resistant tumors with olaparib plus the Pgp inhibitor tariquidar resensitized the tumors to olaparib. Although results in this animal model support a new look at Pgp as a target, in this era of "targeted therapies," trial designs that directly assess modulation of drug uptake, including quantitative nuclear imaging, should be pursued before clinical efficacy assessments are undertaken. Such assessment should be performed with compounds that inhibit tissue Pgp without altering the pharmacokinetics of chemotherapeutic agents. This pharmacodynamic study demonstrated that CBT-1®, inhibits Pgp-mediated efflux from PBMCs and normal liver.
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- 2012
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26. On drug development, chance, and the prepared mind.
- Author
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Bates SE
- Subjects
- Animals, Humans, Antineoplastic Agents therapeutic use, Drug Design, Neoplasms drug therapy
- Published
- 2012
- Full Text
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27. Potential pitfalls of crossover and thoughts on iniparib in triple-negative breast cancer.
- Author
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Fojo T, Amiri-Kordestani L, and Bates SE
- Subjects
- Benzamides therapeutic use, Breast Neoplasms genetics, Breast Neoplasms mortality, Breast Neoplasms pathology, Confounding Factors, Epidemiologic, Disease Progression, Disease-Free Survival, Female, Humans, Indoles therapeutic use, Interferon-gamma therapeutic use, Neoplasms chemistry, Neoplasms drug therapy, Pyrroles therapeutic use, Research Design, Sunitinib, Treatment Outcome, Antineoplastic Agents therapeutic use, Biomarkers, Tumor analysis, Breast Neoplasms chemistry, Breast Neoplasms drug therapy, Cross-Over Studies, Patient Selection, Randomized Controlled Trials as Topic
- Abstract
As recruitment for oncology clinical trials has become more difficult, there appears to have been an increase in the number of studies that allow patients in the control arm to "crossover" and receive the experimental therapy after disease progression. Although some researchers worry that allowing such crossover may abolish gains in progression-free survival in the experimental arm, the possibility that crossover might inadvertently benefit the experimental arm has not been addressed. In clinical trials in which the experimental agent has little or no intrinsic activity and is used to modulate an active combination, such crossover might negatively affect the overall survival of the control arm. Because resistance to the active combination--manifested as disease progression--has occurred, the likelihood of benefit from adding the experimental drug is reduced. Consequently, patients who were randomly assigned to the control arm continue to receive the now inactive combination after crossover, whereas patients in the experimental arm who discontinue study participation may seek out potentially effective salvage regimens. This difference in subsequent therapies may confer an advantage to the experimental arm that is manifested as gains beyond those achieved in progression-free survival, gains that occur not because the experimental therapy induced a change in tumor biology that persists beyond treatment discontinuation but because the control arm suffers by continuing to receive a therapy on which their tumor is progressing. Such an outcome may explain the recently reported trial results for iniparib in triple-negative breast cancer. Given that allowing patients in the control arm to receive the experimental agent may confound interpretation of overall survival, such crossover should not be used indiscriminately, especially if the experimental agent has little or no intrinsic activity.
- Published
- 2011
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28. Prostate cancer: score one for validated targets.
- Author
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Bates SE
- Subjects
- Androstenes, Drug Approval, Humans, Male, Molecular Targeted Therapy, Androstenols therapeutic use, Antineoplastic Agents therapeutic use, Prostatic Neoplasms drug therapy
- Published
- 2011
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29. ABC transporters: unvalidated therapeutic targets in cancer and the CNS.
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Robey RW, Massey PR, Amiri-Kordestani L, and Bates SE
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, ATP-Binding Cassette Transporters genetics, ATP-Binding Cassette Transporters metabolism, Animals, Antineoplastic Agents metabolism, Blood-Brain Barrier, Clinical Trials as Topic, Drug Resistance, Multiple genetics, Humans, Neoplasms metabolism, Polymorphism, Single Nucleotide, Treatment Outcome, ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors, ATP-Binding Cassette Transporters antagonists & inhibitors, Antineoplastic Agents therapeutic use, Central Nervous System metabolism, Drug Resistance, Neoplasm genetics, Molecular Targeted Therapy, Neoplasms drug therapy
- Abstract
The discovery of the multidrug transporter P-glycoprotein (Pgp) over 35 years ago in drug resistant cells prompted several decades of work attempting to overcome drug resistance by inhibition of drug efflux. Despite convincing laboratory data showing that drug transport can be inhibited in vitro, efforts to translate this discovery to the clinic have not succeeded. Since overexpression of Pgp and related transporters including ABCG2 and members of the ABCC family have been linked with poor outcome, it remains a reasonable hypothesis that this poor outcome is linked to reduction of drug exposure by efflux, and thus to drug resistance. In this review, we will discuss the question of whether ABC transporters mediate drug resistance in cancer through a reduction in drug accumulation in tumors, and whether the "Pgp inhibition hypothesis" might be wrong. The hypothesis, which holds that increased chemotherapy effectiveness can be achieved by inhibiting Pgp-mediated drug efflux has only been validated in model systems. Possible explanations for the failure to validate this clinically include the existence of other modulators of drug accumulation and uptake in tumors. Despite these difficulties, a potential role has emerged for drug transporters as therapeutic targets in the central nervous system (CNS). Both lines of investigation point to the need for imaging agents to facilitate the study of drug accumulation in human cancer. This is a critical need for targeted therapies where an important dose-response relationship is likely to exist, and where drug resistance renders many of the novel targeted agents ineffective in a subset of patients.
- Published
- 2010
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30. DNA repair: a reinvigorated therapeutic target.
- Author
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Bates SE
- Subjects
- Antineoplastic Agents pharmacology, Humans, Molecular Targeted Therapy trends, Neoplasms genetics, Therapies, Investigational methods, Therapies, Investigational trends, Antineoplastic Agents therapeutic use, DNA Repair drug effects, DNA Repair genetics, Molecular Targeted Therapy methods, Neoplasms drug therapy
- Published
- 2010
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31. Romidepsin: a new therapy for cutaneous T-cell lymphoma and a potential therapy for solid tumors.
- Author
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Grant C, Rahman F, Piekarz R, Peer C, Frye R, Robey RW, Gardner ER, Figg WD, and Bates SE
- Subjects
- Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacology, Bone Marrow Diseases chemically induced, Clinical Trials, Phase II as Topic, Depsipeptides adverse effects, Depsipeptides pharmacology, Fatigue chemically induced, Gastrointestinal Diseases chemically induced, Gene Targeting, Heart Diseases chemically induced, Histone Deacetylase Inhibitors adverse effects, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases physiology, Humans, Infections etiology, Lymphoma, T-Cell, Cutaneous enzymology, Lymphoma, T-Cell, Cutaneous pathology, Molecular Structure, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins physiology, Neoplasms enzymology, Practice Guidelines as Topic, Antineoplastic Agents therapeutic use, Depsipeptides therapeutic use, Histone Deacetylase Inhibitors therapeutic use, Lymphoma, T-Cell, Cutaneous drug therapy, Neoplasms drug therapy
- Abstract
Romidepsin is a histone deacetylase inhibitor (HDI), approved by the US FDA for the treatment of cutaneous T-cell lymphoma (CTCL). Although various mechanisms have been proposed for the activity of HDIs, including induction of genes controlling cell cycle, acetylation of cytoplasmic proteins and direct induction of apoptosis, the mechanism underlying activity of romidepsin and other HDIs in CTCL is not known. Romidepsin induces long-lasting responses. The side-effect profile is similar to that of other HDIs, causing fatigue, nausea and thrombocytopenia. Management of the CTCL population requires vigilence to prevent infection with skin contaminants, and monitoring of potassium and magnesium, electrolytes found to be low in a large proportion of patients. Electrocardiographic (ECG) changes are common but are not associated with myocardial damage. When molecular end points were evaluated in 61 patients enrolled on a Phase II trial with romidepsin, response was associated with persistence of acetylated histone H3, suggesting that drug exposure is important in effective therapy with romidepsin. Future studies will endeavor to identify combination strategies to increase the efficacy both in resistant CTCL and in solid tumors and to identify biomarkers of response that will allow selection of patients most likely to benefit from the therapy.
- Published
- 2010
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32. A phase II clinical trial of ixabepilone (Ixempra; BMS-247550; NSC 710428), an epothilone B analog, in patients with metastatic renal cell carcinoma.
- Author
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Huang H, Menefee M, Edgerly M, Zhuang S, Kotz H, Poruchynsky M, Huff LM, Bates S, and Fojo T
- Subjects
- Blotting, Western, Female, Humans, Male, Middle Aged, Tubulin drug effects, Antineoplastic Agents therapeutic use, Carcinoma, Renal Cell drug therapy, Epothilones therapeutic use, Kidney Neoplasms drug therapy
- Abstract
Purpose: Ixabepilone (Ixempra; BMS-247550) is an epothilone B analog and nontaxane microtubule-stabilizing compound with clinical activity in a range of solid tumors. This phase II study was conducted to assess the efficacy and safety of ixabepilone in patients with metastatic renal cell carcinoma., Experimental Design: Patients with metastatic renal cell carcinoma who had measurable disease and had not received previous cytotoxic or targeted therapy were treated with 6 mg/m(2) ixabepilone i.v. daily for 5 days every 3 weeks. Levels of Glu-terminated and acetylated tubulin, markers of microtubule stabilization, were assessed by Western blot. VHL gene mutation status was determined by sequencing., Results: Eighty-seven patients received a total of 590 cycles, with a median of 5 cycles (range, 1-29). The overall response rate was 13% (Response Evaluation Criteria in Solid Tumor). One patient had a complete response, 10 patients had partial responses, and 59 patients had stable disease. The median duration of response was 5.5 months. The median overall survival of renal cell carcinoma Motzer grade 0 and 1 patients with clear cell histology was 19.25 months. Treatment-related adverse events were primarily alopecia, gastrointestinal toxicity, neuropathy, and fatigue. Biopsies were done at baseline and after five doses of ixabepilone. Microtubule target engagement was achieved in 84.6% to 92.3% of patients evaluated. No correlation was identified between the target engagement, VHL gene mutation status, and clinical response., Conclusion: Ixabepilone can cause tumor regression in some patients with metastatic renal cell carcinoma and could be considered in combination regimens with other therapies.
- Published
- 2010
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33. Epigenetic modifiers: basic understanding and clinical development.
- Author
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Piekarz RL and Bates SE
- Subjects
- DNA Methylation drug effects, Drug Therapy, Combination, Histone Deacetylases metabolism, Humans, Methyltransferases metabolism, Neoplasms drug therapy, Antineoplastic Agents therapeutic use, Enzyme Inhibitors therapeutic use, Epigenesis, Genetic drug effects, Histone Deacetylase Inhibitors, Methyltransferases antagonists & inhibitors, Neoplasms enzymology
- Abstract
More than 60 years after the first description of differentiation in cell culture and 40 years after the synthesis of 5-azacytidine, epigenetic therapies have been added to the anticancer armamentarium. DNA methyltransferase (DNMT) inhibitors such as 5-aza-2'-deoxycytidine or 5-azacytidine have been approved in myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML), whereas the histone deacetylase inhibitors (HDIs) including vorinostat, romidepsin, panobinostat, belinostat, and entinostat have been shown to be active in cutaneous and peripheral T-cell lymphoma. Although the range of malignancies in which monotherapy with DNMT inhibitors or HDIs are effective has been limited to date, the possibility remains that a broader spectrum of activity will be identified as combination studies are completed. Meanwhile, basic science has provided a steadily increasing understanding of the complexity of the epigenome, including the histone code and triggers for aberrant methylation, and their contribution to oncogenesis. As our basic understanding of the epigenetics of cancer increases, the number of potential therapeutic targets will also increase, offering more hope in the quest to treat cancer by normalizing the epigenome. This issue of CCR Focus is dedicated to understanding the clinical and translational aspects of epigenetics research.
- Published
- 2009
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34. Epigenetic therapies reach main street.
- Author
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Bates SE
- Subjects
- Drug Therapy, Combination, Histone Deacetylase Inhibitors, Histone Deacetylases metabolism, Humans, Neoplasms genetics, Antineoplastic Agents therapeutic use, DNA Methylation drug effects, Enzyme Inhibitors therapeutic use, Epigenesis, Genetic drug effects, Neoplasms drug therapy
- Published
- 2009
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35. Bevacizumab reduces the growth rate constants of renal carcinomas: a novel algorithm suggests early discontinuation of bevacizumab resulted in a lack of survival advantage.
- Author
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Stein WD, Yang J, Bates SE, and Fojo T
- Subjects
- Antibodies, Monoclonal, Humanized, Bevacizumab, Carcinoma, Renal Cell pathology, Cell Growth Processes drug effects, Data Interpretation, Statistical, Disease Progression, Disease-Free Survival, Humans, Kidney Neoplasms pathology, Prognosis, Survival Rate, Treatment Outcome, Antibodies, Monoclonal administration & dosage, Antineoplastic Agents administration & dosage, Carcinoma, Renal Cell drug therapy, Kidney Neoplasms drug therapy, Models, Biological
- Abstract
Background: To hasten cancer drug development, new paradigms are needed to assess therapeutic efficacy. In a randomized phase II study in patients with renal cell carcinoma, 10 microg/kg bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA) administered every 2 weeks resulted in a longer time to progression but a statistically significant difference in overall survival could not be demonstrated., Methods: We developed a novel two-phase equation to estimate concomitant rates of tumor regression (regression rate constant) and tumor growth (growth rate constant). This method allows us to assess therapeutic efficacy using tumor measurements gathered while a patient receives therapy in a clinical trial., Results: The growth rate constants of renal cell carcinomas were significantly lower during therapy with 10 microg/kg bevacizumab than those of tumors in patients receiving placebo. In all cohorts the tumor growth rate constants were correlated with survival. That a survival advantage was not demonstrated with bevacizumab appears to have been a result of early discontinuation of bevacizumab., Conclusions: Single-agent bevacizumab significantly affects the growth rate constants of renal cell carcinoma. Extrapolating from the growth rate constants, we conclude that the failure to demonstrate a survival advantage in the original study was a result of premature discontinuation of bevacizumab. The mathematical model described herein has applications to many tumor types and should aid in evaluating the relative efficacies of different therapies. Quantitating tumor growth rate constants using data gathered while patients are enrolled in a clinical trial, as in the present study, may streamline and assist in drug development.
- Published
- 2008
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36. New cytotoxics in oncology. From the editor.
- Author
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Bates SE
- Subjects
- DNA, Neoplasm drug effects, Humans, Antineoplastic Agents therapeutic use, Medical Oncology trends, Neoplasms drug therapy
- Published
- 2008
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37. Evidence for microtubule target engagement in tumors of patients receiving ixabepilone.
- Author
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Zhuang SH, Hung YE, Hung L, Robey RW, Sackett DL, Linehan WM, Bates SE, Fojo T, and Poruchynsky MS
- Subjects
- Blotting, Western, Cell Line, Tumor, Electrophoresis, Polyacrylamide Gel, Humans, Protein Processing, Post-Translational drug effects, Tubulin drug effects, Antineoplastic Agents therapeutic use, Carcinoma, Renal Cell drug therapy, Epothilones therapeutic use, Kidney Neoplasms drug therapy, Microtubules drug effects, Tubulin analysis
- Abstract
Purpose: Microtubule-stabilizing agents, such as taxanes, have been shown to be effective anticancer drugs. alpha-Tubulin, a basic unit of microtubules, can undergo several posttranslational modifications after assembly into stabilized microtubules, including acetylation and detyrosination. These modifications have been observed in cell cultures after exposure to microtubule stabilizers. Our objective was to develop a straightforward and dependable assay to show tubulin target engagement in tumor tissue after treatment of patients with ixabepilone(BMS-247550; Ixempra)., Experimental Design: Levels of posttranslationally modified alpha-tubulin were assessed in lysates of cultured malignant cell lines, as well as in both tumor tissue and peripheral blood mononuclear cells derived from patients before and after treatment with ixabepilone. Modification-specific antibodies permitted quantitative Western blot analysis., Results: In cultured cell lines, the levels of detyrosinated (glu-terminated) and acetylated alpha-tubulin increased after microtubule stabilization induced by ixabepilone. ixabepilone treatment also induced a 2-fold to 25-fold increase in detyrosinated alpha-tubulin levels in 11 of 13 serial biopsies and a 2-fold to 100-fold increase in acetylated alpha-tubulin in 11 of 12 serial biopsies obtained from patients receiving ixabepilone. Overall, little or no difference in tubulin modifications were observed between the before and after ixabepilone treatment in lysates from their peripheral blood mononuclear cells at the time point examined., Conclusion: Assessing the levels of detyrosinated and/or acetylated alpha-tubulin seems to provide a simple and reliable assay to show target engagement by the microtubule-stabilizing agent ixabepilone. Such analyses may provide further understanding of therapeutic success or failure of microtubule-stabilizing agents in cancer therapy.
- Published
- 2007
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38. Tariquidar (XR9576): a P-glycoprotein drug efflux pump inhibitor.
- Author
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Fox E and Bates SE
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Animals, Humans, Neoplasms drug therapy, Neoplasms epidemiology, Neoplasms metabolism, Protein Transport drug effects, Protein Transport physiology, Quinolines administration & dosage, ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors, Antineoplastic Agents therapeutic use, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Quinolines pharmacology
- Abstract
P-glycoprotein actively transports structurally unrelated compounds out of cells, conferring the multidrug resistance phenotype in cancer. Tariquidar is a potent, specific, noncompetitive inhibitor of P-glycoprotein. Tariquidar inhibits the ATPase activity of P-glycoprotein, suggesting that the modulating effect is derived from the inhibition of substrate binding, inhibition of ATP hydrolysis or both. In clinical trials, tariquidar is tolerable and does not have significant pharmacokinetic interaction with chemotherapy. In patients, inhibition of P-glycoprotein has been demonstrated for 48 h after a single dose of tariquidar. Studies to assess a possible increase in toxicity of chemotherapy and the impact of P-glycoprotein inhibition on tumor response and patient outcome are ongoing. Tariquidar can be considered an ideal agent for testing the role of P-glycoprotein inhibition in cancer.
- Published
- 2007
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39. Association of variant ABCG2 and the pharmacokinetics of epidermal growth factor receptor tyrosine kinase inhibitors in cancer patients.
- Author
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Li J, Cusatis G, Brahmer J, Sparreboom A, Robey RW, Bates SE, Hidalgo M, and Baker SD
- Subjects
- ATP Binding Cassette Transporter, Subfamily G, Member 2, ATP-Binding Cassette Transporters antagonists & inhibitors, ATP-Binding Cassette Transporters genetics, Adult, Amino Acid Substitution, Antineoplastic Agents pharmacology, Biological Transport genetics, Erlotinib Hydrochloride, Gefitinib, Humans, Mutation, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins genetics, Protein Kinase Inhibitors pharmacology, Quinazolines pharmacokinetics, Quinazolines pharmacology, ATP-Binding Cassette Transporters metabolism, Antineoplastic Agents pharmacokinetics, ErbB Receptors antagonists & inhibitors, Neoplasm Proteins metabolism, Neoplasms metabolism, Protein Kinase Inhibitors pharmacokinetics
- Abstract
The purpose of the study was to determine if the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, are substrates for the efflux transporter ABCG2, and to investigate the relevance of the ABCG2 421C>A (Q141K) polymorphism to the pharmacokinetics of gefitinib. Gefitinib and erlotinib transport in vitro was studied using HEK293 cells transfected with wild-type ABCG2 or a Q141K clone. Gefitinib pharmacokinetics was determined in 27 cancer patients. was. ABCG2 421C>A and ABCB1 3435C>T genotypes were determined using direct sequencing. Cells expressing wild-type ABCG2 exhibited lower intracellular accumulation of gefitinib and erlotinib at concentrations of 0.1 and 1 microM, and higher efflux at 1 microM than cells lacking ABCG2 (p < 0.05); no significant difference in cellular efflux and accumulation was observed in the variant cell line at lower concentrations nor in the three cell lines at 10 microM. In the presence of the ABCG2 inhibitor fumitremorgin C, cellular accumulation of gefitinib and erlotinib 1 microM was increased in wild-type (p < 0.05), but not in variant or null cells. Gefitinib accumulation during 28 days of treatment (C(ss,min)/C(1,min)) was higher in patients heterozygous at the ABCG2 421C>A locus than those with a wild-type genotype (median, 5.07 vs. 3.60, p = 0.004). No significant associations were observed between the ABCB1 3435C>T genotype and gefitinib pharmacokinetics. In conclusion, gefitinib and erlotinib are ABCG2 substrates, while they inhibit ABCG2 at higher concentrations. A functional variant of ABCG2 is associated with greater gefitinib accumulation at steady-state and may be relevant to toxicity and antitumor activity of EGFR TKIs.
- Published
- 2007
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40. Toward individualized treatment: prediction of anticancer drug disposition and toxicity with pharmacogenetics.
- Author
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Deeken JF, Figg WD, Bates SE, and Sparreboom A
- Subjects
- Animals, Antineoplastic Agents adverse effects, Carrier Proteins genetics, Carrier Proteins metabolism, Cytochrome P-450 Enzyme System genetics, Cytochrome P-450 Enzyme System metabolism, Humans, Neoplasms genetics, Predictive Value of Tests, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents therapeutic use, Neoplasms drug therapy, Neoplasms metabolism, Pharmacogenetics
- Abstract
A great deal of effort has been spent in defining the pharmacokinetics and pharmacodynamics of investigational and registered anticancer agents. Often, there is a marked variability in drug handling between individual patients, which contributes to variability in the pharmacodynamic effects of a given dose of a drug. A combination of physiological variables, genetic characteristics (pharmacogenetics) and environmental factors is known to alter the relationship between the absolute dose and the concentration-time profile in plasma. A variety of strategies are now being evaluated in patients with cancer to improve the therapeutic index of anticancer drugs by implementation of pharmacogenetic imprinting through genotyping or phenotyping individual patients. The efforts have mainly focused on variants in genes encoding the drug-metabolizing enzymes thiopurine S-methyltransferase, dihydropyrimidine dehydrogenase, members of the cytochrome P450 family, including the CYP2B, 2C, 2D and 3A subfamilies, members of the UDP glucuronosyltransferase family, as well as the ATP-binding cassette transporters ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein). Several of these genotyping strategies have been shown to have substantial impact on therapeutic outcome and should eventually lead to improved anticancer chemotherapy.
- Published
- 2007
- Full Text
- View/download PDF
41. Histone deacetylase inhibitors and demethylating agents: clinical development of histone deacetylase inhibitors for cancer therapy.
- Author
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Piekarz RL, Sackett DL, and Bates SE
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Clinical Trials as Topic, Enzyme Inhibitors adverse effects, Enzyme Inhibitors chemistry, Histone Deacetylases chemistry, Humans, Antineoplastic Agents therapeutic use, Enzyme Inhibitors therapeutic use, Histone Deacetylase Inhibitors
- Abstract
The histone deacetylase inhibitors are a new class of agents that are currently in various stages of clinical development. Clinical trials have demonstrated activity, urging further investigation. At the same time, it has been discovered that these agents have their own challenges. In this review, we discuss clinical data gathered to date, combination therapies designed to increase efficacy, and toxicities attributed to this new class of agents.
- Published
- 2007
- Full Text
- View/download PDF
42. Challenges of evaluating the cardiac effects of anticancer agents.
- Author
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Bates SE, Rosing DR, Fojo T, and Piekarz RL
- Subjects
- Antineoplastic Agents therapeutic use, Humans, Risk Factors, Antineoplastic Agents adverse effects, Heart drug effects, Heart Diseases chemically induced, Neoplasms drug therapy
- Published
- 2006
- Full Text
- View/download PDF
43. Single nucleotide polymorphisms modify the transporter activity of ABCG2.
- Author
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Morisaki K, Robey RW, Ozvegy-Laczka C, Honjo Y, Polgar O, Steadman K, Sarkadi B, and Bates SE
- Subjects
- ATP Binding Cassette Transporter, Subfamily G, Member 2, Cell Culture Techniques, Drug Resistance, Neoplasm, Humans, Kidney cytology, ATP-Binding Cassette Transporters genetics, ATP-Binding Cassette Transporters physiology, Antineoplastic Agents pharmacokinetics, Neoplasm Proteins genetics, Neoplasm Proteins physiology, Polymorphism, Single Nucleotide
- Abstract
Single nucleotide polymorphism (SNP) analyses of the ABCG2 gene have revealed three nonsynonymous SNPs resulting in the amino acid changes at V12M, Q141K and D620N. To determine whether the SNPs have an effect on drug transport, human embryonic kidney cells (HEK-293) were stably transfected with full length ABCG2 coding wild-type or SNP variants of ABCG2. In 4-day cytotoxicity assays with mitoxantrone, topotecan, SN-38 or diflomotecan, cells transfected with wild-type R482 ABCG2 showed IC50 values up to 1.2-fold to 5-fold higher than cells expressing comparable levels of Q141K ABCG2, suggesting that the Q141K SNP affects drug transport. FTC-inhibitable mitoxantrone efflux normalized to ABCG2 surface expression as assayed by the anti-ABCG2 antibody 5D3 was significantly lower in cells transfected with Q141K ABCG2 than in those transfected with wild-type R482 ABCG2 (P = 0.0048). Values for V12M and D620N ABCG2 were comparable to those for wild-type R482 ABCG2. The vanadate-sensitive ATPase activity of ABCG2 was assayed in Sf9 insect cells infected with wild-type or SNP variants of ABCG2. Basal ATPase activity in cells transfected with Q141K ABCG2 was 1.8-fold lower than in cells transfected with wild-type ABCG2, but was comparable among cells expressing wild-type, V12M or D620N ABCG2. Confocal studies of ABCG2 localization revealed higher intracellular staining in the Q141K transfectants than in cells transfected with wild-type or V12M ABCG2. Decreased transport of Hoechst 33342 was observed in Sf9 cells expressing V12M ABCG2; however, this was not true in HEK-293 cells expressing V12M ABCG2. These results suggest that the Q141K SNP affects the transport efficiency of ABCG2 and may result in altered pharmacokinetics or drug-resistance profiles in clinical oncology.
- Published
- 2005
- Full Text
- View/download PDF
44. Effect of a histone deacetylase inhibitor on human cardiac mass.
- Author
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Shizukuda Y, Piekarz RL, Bates SE, Sachdev V, Finkel T, and Rosing DR
- Subjects
- Echocardiography, Humans, Neoplasms drug therapy, Organ Size drug effects, Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Antineoplastic Agents therapeutic use, Depsipeptides administration & dosage, Depsipeptides adverse effects, Depsipeptides therapeutic use, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors adverse effects, Enzyme Inhibitors therapeutic use, Heart drug effects, Histone Deacetylase Inhibitors
- Published
- 2005
- Full Text
- View/download PDF
45. T-cell lymphoma as a model for the use of histone deacetylase inhibitors in cancer therapy: impact of depsipeptide on molecular markers, therapeutic targets, and mechanisms of resistance.
- Author
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Piekarz RL, Robey RW, Zhan Z, Kayastha G, Sayah A, Abdeldaim AH, Torrico S, and Bates SE
- Subjects
- Cell Line, Tumor, Cell Survival drug effects, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic drug effects, Humans, Antineoplastic Agents toxicity, Enzyme Inhibitors toxicity, Histone Deacetylase Inhibitors, Lymphoma, T-Cell pathology, Oligopeptides toxicity
- Abstract
Depsipeptide (FK228) is a novel histone deacetylase inhibitor currently in clinical trials and the first to demonstrate clinical activity in patients. Responses have been observed in patients with T-cell lymphomas, despite prior treatment with multiple chemotherapeutic agents. To better understand the effects of histone deacetylase inhibitors on T-cell lymphoma, the human T-cell lymphoma cell line HUT78 was tested for sensitivity and molecular response to depsipeptide. Treatment with depsipeptide, as well as other histone deacetylase inhibitors, caused induction of histone acetylation, induction of p21 expression, and substantial apoptosis without significant cell cycle arrest. Treatment with the caspase inhibitor z-VAD-fmk significantly inhibited depsipeptide-induced apoptosis, enabling detection of cell cycle arrest. Treatment with depsipeptide increased expression of the interleukin-2 (IL-2) receptor, and combination with the IL-2 toxin conjugate denileukin diftitox resulted in more than additive toxicity. Cells selected for resistance to depsipeptide overexpressed the multidrug resistance pump, P-glycoprotein (Pgp). However, cells selected for resistance to depsipeptide in the presence of a Pgp inhibitor had a Pgp-independent mechanism of resistance. These studies confirm the activity of depsipeptide in a T-cell lymphoma model and suggest a general sensitivity of T-cell lymphoma to histone deacetylase inhibitors, an emerging new class of anticancer agents.
- Published
- 2004
- Full Text
- View/download PDF
46. A review of depsipeptide and other histone deacetylase inhibitors in clinical trials.
- Author
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Piekarz R and Bates S
- Subjects
- Antineoplastic Agents administration & dosage, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Clinical Trials as Topic, Humans, Peptides, Cyclic administration & dosage, Peptides, Cyclic therapeutic use, Antineoplastic Agents pharmacology, Depsipeptides, Histone Deacetylase Inhibitors, Peptides, Cyclic pharmacology
- Abstract
The histone deacetylase inhibitors (HDIs) are a new class of antineoplastic agents currently being evaluated in clinical trials. While these agents have been studied extensively in the laboratory, only recently has their mechanism of action begun to be elucidated. Several structural classes of compounds have been shown to exert histone deacetylase inhibition, including sodium n-butyrate, suberoylanilide hydroxamic acid, LAQ824, CI-994, MS-275, and depsipeptide. The HDIs have been shown to induce differentiation, to decrease cell proliferation, and to induce cell death. HDIs are thought to exert their anti-neoplastic effects by altering the expression of genes that play a role in the control of cell growth, and transformation. The HDIs have specific and well-defined effects on cancer cells. Preliminary results from clinical trials suggest that these agents are very promising. While there were sporadic case reports of activity using the early generation HDIs, dramatic responses have recently been observed in patients with T-cell lymphomas treated with depsipeptide, one of the newer agents. With the well-defined molecular effects on cancer cells, surrogate markers can be analyzed for evidence of activity and efficacy using either tumor samples or normal tissue. Presented in this review are details from clinical trials with both earlier and newer generations of HDIs. Toxicities specific to this class of agents are outlined and possibilities for rational combination therapies are discussed.
- Published
- 2004
- Full Text
- View/download PDF
47. Low and high concentrations of the topo II inhibitor daunorubicin in NIH3T3 cells: reversible G2/M versus irreversible G1 and S arrest.
- Author
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Stein WD, Robey R, Cardarelli C, Gottesman MM, and Bates SE
- Subjects
- Antineoplastic Agents administration & dosage, Cell Cycle drug effects, Cell Differentiation, Cell Line, DNA Topoisomerases, Type II metabolism, Daunorubicin administration & dosage, Dose-Response Relationship, Drug, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors pharmacology, G1 Phase drug effects, G2 Phase drug effects, Humans, Mitosis drug effects, S Phase drug effects, Antineoplastic Agents pharmacology, Daunorubicin pharmacology, Topoisomerase II Inhibitors
- Abstract
Daunorubicin (DNR) blocks the cell cycle by interfering with synthesis and repair of DMA. In both drug-sensitive 3T3 cells and drug-resistant 3T3 cells (NIH-MDR-6185, created by transfection with a human MDR1 cDNA), low concentrations of DNR (up to 80 ng/ml in sensitive cells, 1600 ng/ml in resistant cells) initially slowed S-phase progression for 2 to 3 hours, but the treated cells then continued in progression at a steady rate, close to that of untreated cells, and accumulated in G(2)/M. The 2 to 3 h lag period represents the time taken for fully establishing the G(2)/M block. The time required to bring about cessation of proliferation is the sum of this lag period and the time taken to travel through the cell cycle. This low concentration effect is cytostatic, and fully reversible on washing out the daunorubicin. At higher drug concentrations (above 160 ng/ml in sensitive cells, 3200 ng/ml in resistant cells) the cells became blocked in both G] and S, and did not reach G(2)/M. The high concentration effect was cytotoxic and irreversible, and was followed by cell death. Only cells that were in S phase were subject to this block in S, since cells that had accumulated in G(2)/M by using a low concentration (60 ng/ml DNR for 20 h) were not blocked in S, and did not die, when subsequently treated with high drug concentrations (320 ng/ml, 30 h). The low concentration effect occurred at the same maximal rate (4 %/h) in sensitive or resistant cells, but the external drug concentration required to produce half the maximal rate was, appropriately, twenty-fold higher in the resistant cells (20 ng/ml and 400 ng/ml, respectively).
- Published
- 2003
48. ABC transporters and inhibitors: new targets, new agents.
- Author
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Leonard GD, Polgar O, and Bates SE
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors, ATP Binding Cassette Transporter, Subfamily B, Member 1 biosynthesis, ATP-Binding Cassette Transporters biosynthesis, Animals, Antineoplastic Agents pharmacology, Clinical Trials as Topic statistics & numerical data, Drug Resistance, Multiple physiology, Humans, ATP-Binding Cassette Transporters antagonists & inhibitors, Antineoplastic Agents therapeutic use, Drug Delivery Systems methods
- Abstract
P-glycoprotein (P-gp), a plasma membrane pump associated with multidrug resistance (MDR), is a member of the superfamily of ATP-binding cassette (ABC) transporters. The discovery that inhibitors of drug efflux can increase drug accumulation and reverse drug resistance in the laboratory has led to the clinical development of a number of P-gp inhibitors. Initial studies were performed with agents already in use in the clinic for other indications, the 'first generation' studies. Second generation inhibitors were taken into clinical trials in leukemia, breast cancer, ovarian cancer and sarcoma, malignancies for which there is evidence that P-gp is expressed, and in some cases, associated with a poorer therapeutic outcome. One major limitation of these trials, however, was the reduction in anticancer drug doses that was required with concurrent administration of inhibitor. The reduction in drug dose needed in these combination studies, may have confounded the results and contributed to disappointing outcomes. Functional assays to verify the role of P-gp inhibition in MDR, such as sestamibi imaging are proving helpful in assessing the development of improved inhibitors that are providing hope for the future. This review focuses on attempts aimed at overcoming resistancemediated by ABC transporters and evaluates the prospects for addition of new inhibitors to the anticancer armamentarium.
- Published
- 2002
49. MS-27-275, an inhibitor of histone deacetylase, has marked in vitro and in vivo antitumor activity against pediatric solid tumors.
- Author
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Jaboin J, Wild J, Hamidi H, Khanna C, Kim CJ, Robey R, Bates SE, and Thiele CJ
- Subjects
- Acetylation drug effects, Animals, Cell Cycle drug effects, Child, DNA, Neoplasm biosynthesis, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Gene Expression Regulation, Neoplastic drug effects, Histones metabolism, Humans, Mice, Mice, Nude, Mice, SCID, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Benzamides pharmacology, Enzyme Inhibitors pharmacology, Histone Deacetylase Inhibitors, Pyridines pharmacology
- Abstract
The antitumor efficacy of the synthetic benzamide derivative MS-27-275 (MS-275), an inhibitor of histone deacetylation [T. Suzuki et al., J. Med. Chem., 42: 3001-3003, 1999], was evaluated in a series of pediatric solid tumor cell lines, including neuroblastoma, rhabdomyosarcoma, Ewing's sarcoma (EWS), retinoblastoma, medulloblastoma, undifferentiated sarcoma (US), osteosarcoma, and malignant rhabdoid tumors. Treatment with MS-275 results in an increase in acetylation of histones within 4 h of drug exposure. The cell lines were treated with various concentrations of MS-275 for 3 days and incubated with [(3)H]thymidine for 20 h before cell harvest. MS-275 inhibited [(3)H]thymidine uptake in a dose-dependent manner in all tumor cell lines examined. The IC(50) ranged from 50 nm in the D283 medulloblastoma cell line to 1.3 micro M in the US. A common feature of MS-275 treatment of pediatric tumor cell lines was induction of p21mRNA. However, the effects on cell cycle were diverse because in some cases MS-275 induced an increase in G(1) or G(2), whereas in others, there was an induction of apoptosis. In EWS, the EWS/fli chimeric transcription factor created by the t(11;22) suppresses transforming growth factor (TGF) betaRII transcription, however, MS-275 was able to induce an increase in TGF-betaRII mRNA and restore TGF-beta signaling. Using xenograft orthotopic models of US, EWS, and neuroblastoma, we find that the growth of established tumors is inhibited in mice treated with MS-275.
- Published
- 2002
50. Arsenic trioxide (As(2)O(3)): still a mystery.
- Author
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Fojo T and Bates S
- Subjects
- Apoptosis, Arsenic Trioxide, Cell Differentiation, Enzyme Activation, Humans, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases metabolism, Proto-Oncogene Proteins c-bcl-2 metabolism, Tumor Cells, Cultured, p38 Mitogen-Activated Protein Kinases, Antineoplastic Agents therapeutic use, Arsenicals therapeutic use, Cell Cycle drug effects, Down-Regulation, Leukemia, Promyelocytic, Acute drug therapy, Oxides therapeutic use
- Published
- 2002
- Full Text
- View/download PDF
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