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Dinaciclib (SCH727965) is a selective CDKi chosen for clinical development based upon a favorable therapeutic index in cancer xenograft models. We performed a phase I dose escalation study of dinaciclib in relapsed and refractory chronic lymphocytic leukemia (CLL) patients with intact organ function and WBC<200 × 10(9) /l. Five separate dose levels (5 mg/m(2), 7 mg/m(2), 10 mg/m(2), 14 mg/m(2) and 17 mg/m(2)) were explored dosing on a weekly schedule × 3 with 1 week off (4-week cycles) using a standard 3+3 design with expansion cohorts to optimize safety. Fifty-two patients were enrolled with relapsed and refractory CLL. Escalation through cohorts occurred with two dose-limiting toxicity (DLTs) at the 17 mg/m(2) dose (tumor lysis syndrome (TLS) and pneumonia). The phase II expansion occurred at 14 mg/m(2) with 16 patients receiving this dose with one DLT (TLS). Additional stepped up dosing to the maximum tolerated dose was examined in 19 patients at this dose. Adverse events included cytopenias, transient laboratory abnormalities and TLS. Responses occurred in 28 (54%) of patients independent of del(17)(p13.1) with a median progression-free survival of 481 days. Dinaciclib is clinically active in relapsed CLL including those patients with high risk del(17)(p13.1) disease and warrants future study. [ABSTRACT FROM AUTHOR]

The article presents a study which evaluates mitochondrial functionality in apoptosis signaling for chronic lymphocytic leukemia (CLL) patient response to alvocidib (flavopiridol). It states that tumor lysis syndrome (TLS) occurrence was found to be related with Bad priming, which gained from inclusion of patient age. The single-agent activity in relapsed/ refractory CLL patients demonstrated by Alvocidib is cited.

Identification of agents that target human leukemia stem cells is an important consideration for the development of new therapies. The present study demonstrates that rocaglamide and silvestrol, closely related natural products from the flavagline class of compounds, are able to preferentially kill functionally defined leukemia stem cells, while sparing normal stem and progenitor cells. In addition to efficacy as single agents, flavaglines sensitize leukemia cells to several anticancer compounds, including front-line chemotherapeutic drugs used to treat leukemia patients. Mechanistic studies indicate that flavaglines strongly inhibit protein synthesis, leading to the reduction of short-lived antiapoptotic proteins. Notably though, treatment with flavaglines, alone or in combination with other drugs, yields a much stronger cytotoxic activity toward leukemia cells than the translational inhibitor temsirolimus. These results indicate that the underlying cell death mechanism of flavaglines is more complex than simply inhibiting general protein translation. Global gene expression profiling and cell biological assays identified Myc inhibition and the disruption of mitochondrial integrity to be features of flavaglines, which we propose contribute to their efficacy in targeting leukemia cells. Taken together, these findings indicate that rocaglamide and silvestrol are distinct from clinically available translational inhibitors and represent promising candidates for the treatment of leukemia. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented concerning the impact of salvage therapy on patients with chronic lymphocytic leukemia and relapsed del(17p13.1) karyotype.

Purpose: Non-small-cell lung cancer (NSCLC) accounts for the majority of lung cancer and is the most common cause of cancer death in industrialized countries. Epigenetic modifications are observed universally during the tumorigenesis of lung cancer. The development of epigenetic-modulating agents utilizing the synergism between hypomethylating agents and histone deacetylase (HDAC) inhibitors provides a novel therapeutic approach in treating NSCLC.Methods: We performed a phase I trial combining 5-aza-2'-deoxycytidine (decitabine) and valproic acid (VPA), in patients with advanced stage NSCLC. Patients were treated with escalating doses of decitabine (5-15 mg/m(2)) IV for 10 days in combination with VPA (10-20 mg/kg/day) PO on days 5-21 of a 28-day cycle. Pharmacokinetic and pharmacodynamic analysis included decitabine pharmacokinetics and fetal hemoglobin expression.Results: Eight patients were accrued to this phase I study. All patients had advanced NSCLC and had received prior chemotherapy. Eastern Cooperative Oncology Group performance status was 0-2. Major toxicities included myelosuppression and neurotoxicity. Dose-limiting toxicity was seen in two patients suffering grade 3 neurotoxicity during cycle one including disorientation, lethargy, memory loss, and ataxia at dose level 1. One patient had grade 3 neutropenia at the de-escalated dose. No objective response was observed, and stable disease was seen in one patient. Fetal hemoglobin levels increased after cycle one in all seven patients with evaluable results.Conclusions: We observed that decitabine and valproic acid are an effective combination in reactivating hypermethylated genes as demonstrated by re-expressing fetal hemoglobin. This combination in patients with advanced stage IV NSCLC, however, is limited by unacceptable neurological toxicity at a relatively low dosage. Combining hypomethylating agents with alternative HDAC inhibitors that lack the toxicity of VPA should be explored further. [ABSTRACT FROM AUTHOR]

Purpose: Non-small-cell lung cancer (NSCLC) accounts for the majority of lung cancer and is the most common cause of cancer death in industrialized countries. Epigenetic modifications are observed universally during the tumorigenesis of lung cancer. The development of epigenetic-modulating agents utilizing the synergism between hypomethylating agents and histone deacetylase (HDAC) inhibitors provides a novel therapeutic approach in treating NSCLC. Methods: We performed a phase I trial combining 5-aza-2′-deoxycytidine (decitabine) and valproic acid (VPA), in patients with advanced stage NSCLC. Patients were treated with escalating doses of decitabine (5-15 mg/m) IV for 10 days in combination with VPA (10-20 mg/kg/day) PO on days 5-21 of a 28-day cycle. Pharmacokinetic and pharmacodynamic analysis included decitabine pharmacokinetics and fetal hemoglobin expression. Results: Eight patients were accrued to this phase I study. All patients had advanced NSCLC and had received prior chemotherapy. Eastern Cooperative Oncology Group performance status was 0-2. Major toxicities included myelosuppression and neurotoxicity. Dose-limiting toxicity was seen in two patients suffering grade 3 neurotoxicity during cycle one including disorientation, lethargy, memory loss, and ataxia at dose level 1. One patient had grade 3 neutropenia at the de-escalated dose. No objective response was observed, and stable disease was seen in one patient. Fetal hemoglobin levels increased after cycle one in all seven patients with evaluable results. Conclusions: We observed that decitabine and valproic acid are an effective combination in reactivating hypermethylated genes as demonstrated by re-expressing fetal hemoglobin. This combination in patients with advanced stage IV NSCLC, however, is limited by unacceptable neurological toxicity at a relatively low dosage. Combining hypomethylating agents with alternative HDAC inhibitors that lack the toxicity of VPA should be explored further. [ABSTRACT FROM AUTHOR]

The article presents a study which describes that dinaciclib has dramatic pre-clinical activity in chronic lymphocytic leukemia (CLL) by justifying its development as a potential clinical candidate agent in CLL. The results of the study suggest that soluble survival signals offered by the microenvironment are antagonized by dinaciclib. The authors also reveal that dinaciclib downregulates mRNA and protein expression of the important anti-apoptotic protein MCL-1 independently of caspases.

Tumor lysis syndrome (TLS) has been described in over 40% of patients with chronic lymphocytic leukemia treated with the cyclin-dependent kinase inhibitor, flavopiridol. We conducted a retrospective analysis to determine predictive factors for TLS. In 116 patients, the incidence of TLS was 46% (95% CI: 36-55%). In univariable analysis, female gender, greater number of prior therapies, Rai stages III-IV, adenopathy ≥ 10 cm, splenomegaly, del(11q), decreased albumin and increased absolute lymphocyte count, white blood cell count (WBC), β2-microglobulin, and lactate dehydrogenase were associated (P < 0.05) with TLS. In multivariable analysis, female gender, adenopathy ≥ 10 cm, elevated WBC, increased β2-microglobulin, and decreased albumin were associated with TLS (P < 0.05). With respect to patient outcomes, 49 and 44% of patients with and without TLS, respectively, responded to flavopiridol (P = 0.71). In a multivariable analysis, controlling for number of prior therapies, cytogenetics, Rai stage, age and gender, progression-free survival (PFS) was inferior in patients with TLS (P = 0.01). Female patients and patients with elevated β2-microglobulin, increased WBC, adenopathy ≥ 10 cm and decreased albumin were at highest risk and should be monitored for TLS with flavopiridol. TLS does not appear to be predictive of response or improved PFS in patients receiving flavopiridol. [ABSTRACT FROM AUTHOR]

Alemtuzumab (anti-CD52; Campath-1H) is effective in fludarabine-refractory chronic lymphocytic leukemia (CLL), but is associated with infection and early onset neutropenia. To reduce toxicity, filgrastim (G-CSF) was administered concurrently with alemtuzumab. In total, 14 CLL patients (median age 59) with a median of 3.5 prior regimens (range 1–12) received i.v. alemtuzumab, stepped up from 3 to 30 mg the first week, then 30 mg thrice weekly for 12 weeks. Filgrastim 5 μg/kg was administered daily 5 days before and throughout alemtuzumab therapy. Six patients developed cytomegalovirus (CMV) reactivation 3–6 weeks into treatment; six patients developed fever, three neutropenia, and one pneumonia. The patient with CMV pneumonia died; ganciclovir cleared CMV in the other patients. Five patients developed early neutropenia (weeks 2–5). Four patients developed delayed neutropenia (weeks 10–13) unassociated with CMV reactivation. Nine patients ceased therapy because of infectious and hematologic toxicity. Five partial responses were noted, all in patients with lymph nodes >5 cm, lasting a median of 6.5 months (range 5–13). Filgrastim and alemtuzumab were given concurrently with manageable infusion toxicity and clinical activity, but the efficacy of this regimen was limited by delayed neutropenia of unclear etiology and CMV reactivation. Filgrastrim should not be administered prophylactically during alemtuzumab therapy outside clinical trials.Leukemia (2005) 19, 1207–1210. doi:10.1038/sj.leu.2403782 Published online 28 April 2005 [ABSTRACT FROM AUTHOR]

In t(8;21) acute myeloid leukemia (AML), the AML1/ETO fusion protein promotes leukemogenesis by recruiting histone deacetylase (HDAC) and silencing AML1 target genes important for hematopoietic differentiation. We hypothesized that depsipeptide (FR901228), a novel HDAC inhibitor evaluated in ongoing clinical trials, restores gene transcription and cell differentiation in AML1/ETO-positive cells. A dose-dependent increase in H3 and H4 histone acetylation was noted in depsipeptidetreated AML1/ETO-positive Kasumi-1 cells and blasts from a patient with t(8;21) AML. Consistent with this biological effect, we also showed a dose-dependent increase in cytotoxicity, expression of IL-3, here used as read-out for silenced AML1target genes, upregulation of CD11b with other morphologic changes suggestive of partial cell differentiation in Kasumi-1 cells. Some of these biologic effects were also attained in other myeloid leukemia cell lines, suggesting that depsipeptide has differentiation and cytotoxic activity in AML cells, regardless of the underlying genomic abnormality. Notably, the activity of depsipeptide was enhanced by 5-aza-2'-deoxycytidine, a DNA methyltransferase inhibitor (DNMT). These two agents in combination resulted in enhanced histone acetylation, IL-3 expression, and cytotoxicity, suggesting HDAC and DNMT activities as a potential dual target in future therapeutic strategies for AML1/ETO and other molecular subgroups of AML. [ABSTRACT FROM AUTHOR]

Although T cell depletion of allografts used in BMT has reduced GVHD, it has been associated with inferior engraftment and an increased risk of relapse. We have found that T cell depletion by counterflow centrifugal elutriation (CCE) also results in depletion of CD34+ stem cells. In order to determine if the discarded CD34+ cells would improve engraftment, we undertook a phase II trial of allogeneic BMT in which 110 patients (median age 43) with a variety of hematologic malignancies received CD34+ stem cell augmented, elutriated marrow grafts. The T cell-depleted grafts were tightly controlled and contained a mean of 4.3 × 107 mononuclear cells/kg, 3.3 × 106 CD34+ cells/kg, 1.5 × 105 CFU-GM/kg and 5.5 × 105 CD3+ T cells/kg. Median time to engraftment of granulocytes (>500/μl) was 16 days and of platelets (>50 000/μl) was 25 days, comparable to that seen with unmanipulated marrow. No mixed hematopoietic chimerism was observed that was not associated with disease relapse. The four patients (3.6%) who failed to engraft were all at high risk because of prior donor transfusions or underlying marrow disorders. The incidence of GVHD was dependent on the duration of cyclosporin A (CsA) immunosuppression. In patients who received CsA for 80 days, the incidence of clinically significant acute GVHD (>stage 1) and extensive, chronic GVHD was 5% and 11%, respectively. Peri-transplant (100 day post-BMT) mortality for this group of patients was 15%. Event-free survival in selected subsets of patients compared favorably to previous studies in which patients received unmanipulated marrow allografts. [ABSTRACT FROM AUTHOR]

The plasma pharmacokinetics of the anti-tumor antibiotic geldanamycin (GM: NSC 122750), a naturally occurring benzoquinoid ansamycin, was characterized in mice and a beagle dog. Concentrations of GM well above 0.1 microgram/ml, which was typically effective against neoplastic cell lines responsive to the drug in vitro, were achieved in the plasma of the mice and the dog treated by i.v. injection. However, the systemic duration of the drug was relatively short. Plasma levels decayed below 0.1 microgram/ml within 3-4 h after administration of the apparent maximum tolerated doses, which were approximately 20 mg/kg for the mice and 4 mg/kg for the dog. The drug exhibited linear pharmacokinetic behavior within the dose ranges studied. However, there were significant interspecies differences in its disposition. Whereas the mean biological half-life of GM was slightly longer in the mice (77.7 min) than in the dog (57.9 min), its mean residence time in the dog (46.6 min) was more than twofold greater than that observed in the mice (20.7 min). Nevertheless, the drug was cleared from plasma much faster by the dog (49.4 ml/min per kg) than by the mice (30.5 ml/min per kg). These apparent anomalies were principally associated with differences in the relative significance of the terminal phase upon overall drug disposition. The liver appeared to be the principal target organ of acute drug toxicity in the dog. Doses of 2.0 and 4.2 mg/kg both produced elevations in serum levels of the transaminases and other indicators of liver function characteristic of acute hepatic necrosis. Additional effects included symptoms of minor gastrointestinal toxicity and alterations in serum chemistry parameters consistent with less severe nephrotoxicity. Drug-related toxicity appeared to be reversible. In consideration of the potential for acute hepatotoxic reactions to GM, as well as to the other benzoquinoid ansamycins based upon structural analogy, additional pharmacological and therapeutic information is required to ascertain whether these compounds are viable candidates for clinical development. [ABSTRACT FROM AUTHOR]

O6-Benzylguanine effectively inactivates the DNA-repair protein O6-alkylguanine-DNA alkyltransferase in tumor cells and has been shown to increase the cytotoxicity of chloroethylnitrosoureas. This study was undertaken to ascertain the optimal vehicle for further toxicological evaluation and eventual clinical trials of O6-benzylguanine. The solubility, metabolism, bioavailability and effectiveness of O6-benzylguanine as an adjuvant therapy with BCNU were compared using two vehicles, cremophor-EL and PEG 400. Nude mice bearing s.c. D456 MG glioblastoma xenografts were injected i.p. with 10-30 mg/kg O6-benzylguanine dissolved in either 40% PEG 400/saline or 10% cremophor-EL/saline. The number of tumor regressions noted after treatment with 10 mg/kg O6-benzylguanine followed by 12.7 mg/kg BCNU were 8/9 for the drug dissolved in PEG and 1/10 for the drug given in cremophor-EL. Using the same treatment regimen but increasing the dose of O6-benzylguanine to 30 mg/kg led to a growth delay of 45.2 and 11.5 days for the drug dissolved in PEG 400 and cremophor-EL, respectively, although the number of regressions observed were the same for both treatments. 8-[3H]-O6-Benzylguanine was more rapidly distributed to the tumor when it was delivered in PEG vehicle than when it was given in cremophor-EL. In contrast, there was a 3-fold greater amount of O6-benzylguanine in the small intestine of mice at 1 h after i.p. injection of the drug in cremophor-EL as compared with PEG 400. The rate and extent of metabolism in the liver was the same, whether the parent drug was given in PEG 400 or in cremophor-EL. These studies demonstrate that O6-benzylguanine is a more effective enhancer of the antitumor activity of BCNU when it is given in PEG 400 than when it is delivered in cremophor-EL, which may be due to a more rapid distribution of the drug to the tumor. [ABSTRACT FROM AUTHOR]

A variety of compounds inhibit the growth and induce differentiation of human promyelocytic leukemia (HL-60) cells. HL-60 subclones that lack the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) can also be induced to differentiate with purine analogs. Mechanisms by which purine analogs induce differentiation offer unique possibilities for cancer chemotherapy. We have studied the effect of the purine analog 6-ethylmercaptopurine (e6MP) on the growth and induction of differentiation in both wild-type and HGPRT-deficient HL-60 cells. We have previously shown that e6MP inhibits cell growth in both wild-type and HGPRT-deficient HL-60 cells without activation through salvage pathways. In this report we evaluate the effect of e6MP on c-myc mRNA expression. c-Myc mRNA, which is amplified in HL-60 cells, has been shown to play a role in the induction of granulocytic differentiation in HL-60 cells. e6MP transiently down-regulates c-myc mRNA in wild-type cells but has no effect on c-myc mRNA expression in HGPRT-deficient HL-60 cells. Despite the differential effects of e6MP on c-myc mRNA, both wild-type and HGPRT-deficient HL-60 cells appear to engage in terminal differentiation. The morphological changes and nonspecific esterase activity induced by e6MP suggest differentiation down the monocytic pathway. However, early monocytic markers such as the rapid induction of c-fos and the stabilization of c-fms mRNA are not observed. In addition, e6MP inhibits TPA-induced monocytic/macrophage differentiation as characterized by stabilization of c-fms mRNA and cellular adherence. [ABSTRACT FROM AUTHOR]

The high interest in natural products as sources of pharmaceutical products led to the creation of the National Cooperative Natural Products Drug Discovery Group (NCNPDDG) Program by the National Cancer Institute with the goal of bringing together scientists from academia, industry and government in afocussed effort for discovery of new drugs for cancer treatment. Similarly, the National Institutes of Health, the National Science Foundation, and the U.S. Agency for International Development have joined together to form the International Cooperative Biodiversity Group (ICBG) program to promote the goals of biodiversity conservation, economic development and pharmaceutical discovery. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article regarding the effect of genetic features on patients with relapsed or refractory chronic lymphocytic leukemia treated with flavopiridol in the 2012 issue.