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Describe the clinical and epidemiological data from young women with breast cancer and determine the association between ethnicity, insurance status, family income, and breast cancer stage at the diagnosis in this population. Women under the age of 40 diagnosed with invasive breast cancer from 2010 to 2014 and identified in the Surveillance, Epidemiology, and End Results (SEER) 18 registries database were included. Binary logistic regression was applied in order to estimate the odds ratios (ORs) for factors that were potentially predictive for receiving a breast cancer diagnosis at stage I. Of 14,379 young women with invasive breast cancer, 70.9% of the patients were white, 15.9% black, and 13.2% classified as other ethnicity (American Indian, Asian, Pacific Islander). The initial clinical stage at diagnosis was stage I in 28.2%, II in 45.2%, III in 19.0%, and IV in 7.6%. The chi-square test showed a significant association between clinical stage at diagnosis and family income (p< 0.0001), insurance status (p< 0.0001), and ethnicity (p< 0.0001). The ORs for being diagnosed at stage I, regarding different factors, revealed that women with family income higher than US$ 85,000 were more likely to be diagnosed with stage I (OR [95%CI], 1.306 [1.173–1.454]; pvalue < 0.0001) when compared with patients with family income of less than US$ 60,000. Black women were less likely to be diagnosed with stage I (OR [95%CI], 0.676 [0.605–0.755]; pvalue < 0.0001), when compared with white women. Uninsured women were less likely to be diagnosed with stage I (OR [95%CI], 0.586 [0.529–0.648]; pvalue < 0.0001) when compared with women with insurance coverage. Among young US women diagnosed with invasive breast cancer, most of them presented early stage disease. Women with black ethnicity, low income, and uninsured are at risk for late-stage presentation. Improvements in strategies to allow earlier breast cancer diagnosis in these at risk population are urged.

Background: Irinotecan (IRI) is a widely used chemotherapeutic drug, mostly used for first-line treatment of colorectal and pancreatic cancer. IRI doses are usually established based on patient’s body surface area, an approach associated with large inter-individual variability in drug exposure and high incidence of severe toxicity. Toxic and therapeutic effects of IRI are also due to its active metabolite SN-38, reported to be up to 100 times more cytotoxic than IRI. SN-38 is detoxified by the formation of SN-38 glucuronide, through UGT1A1. Genetic polymorphisms in the UGT1A1 gene are associated to higher exposures to SN-38 and severe toxicity. Pharmacokinetic models to describe IRI and SN-38 kinetic profiles are available, with few studies exploring pharmacokinetic and pharmacogenetic-based dose individualization. The aim of this manuscript is to review the available evidence supporting pharmacogenetic and pharmacokinetic dose individualization of IRI in order to reduce the occurrence of severe toxicity during cancer treatment. Methods: The PubMed database was searched, considering papers published in the period from 1995-2017, using the keywords irinotecan, pharmacogenetics, metabolic genotyping, dose individualization, therapeutic drug monitoring, pharmacokinetics and pharmacodynamics, either alone or in combination, with original papers being selected based on the presence of relevant data. Conclusion: The findings of this review confirm the importance of considering individual patient characteristics to select IRI doses. Currently, the most straightforward approach for IRI dose individualization is UGT1A1 genotyping. However, this strategy is sub-optimal due to several other genetic and environmental contributions to the variable pharmacokinetics of IRI and its active metabolite. The use of dried blood spot sampling could allow the clinical application of limited sampling and population pharmacokinetic models for IRI doses individualization.

To evaluate the safety, tolerability and potential therapeutic effects of gastrin‐releasing peptide in three children with autistic spectrum disorder.

To evaluate the safety, tolerability and potential therapeutic effects of gastrin-releasing peptide in three children with autistic spectrum disorder.

Nanoliposomal irinotecan showed activity in a phase 2 study in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapies. We assessed the effect of nanoliposomal irinotecan alone or combined with fluorouracil and folinic acid in a phase 3 trial in this population.

Gastrin-releasing peptide is a neuroendocrine homolog of bombesin that demonstrated important growth-stimulatory effects in various types of cancer. High levels of expression of gastrin-releasing peptide receptors (GRPR) has been found in different malignancies, and the studies exploring the therapeutic use of GRPR antagonists have shown promising results. Our aim was to determine the GRPR expression in epidermoid carcinoma of the anal canal and discuss its potential clinical applications. We performed immunohistochemical analysis for GRPR on formalin-fixed and paraffin-embedded tumor samples obtained from 35 patients with anal cancer. As a control group, we analyzed 24 samples of nonmalignant anal tissues (hemorrhoidectomy specimens). GRPR expression was evaluated using a semiquantitative approach according to the intensity and distribution of staining. All analyzed tissues, except 1 control sample, showed positive GRPR immunoexpression. GRPR was strongly expressed in 54 of cancer specimens as compared with only 12 of the control specimens (P<0.003). In tumors, the receptor showed a diffuse and homogenous pattern of distribution within the specimens. In contrast, control specimens showed a focal pattern of staining restricted to the basal half of the epithelium. In conclusion, we demonstrated that GRPR is highly expressed in epidermoid carcinoma of the anal canal, suggesting this receptor might have a role in anal carcinogenesis. Our results provide a basis for exploiting GRPR as a target for diagnostic and therapeutic purposes in the anal cancer.

A large number of plants are known to possess strong antitumor properties. Previous studies have verified the antiproliferative activity of the extracts and fractions from six species of Hypericumspp. growing in southern Brazil. In the present study, the in-vitro antiproliferative effects of two dimeric phloroglucinols (japonicin A and uliginosin B, isolated from Hypericum myrianthum) and two benzophenones (cariphenone A and cariphenone B, isolated from H. carinatum) were investigated against three tumor cell lines (HT-29 – human colon carcinoma cells; U-251 – human glioma cell line, and OVCAR-3 – human ovarian carcinoma cells). In addition, different doses of these compounds were associated with cytotoxic drugs commonly used as chemotherapy in the clinic. Cariphenone A and cariphenone B showed moderate antiproliferative activity against all tumor cell lines at a dose of 100 gml. Unlike benzophenones, japonicin A and uliginosin B exerted antiproliferative effects only in the OVCAR-3 cell line. Moreover, a very strong synergistic effect was demonstrated by the association of subeffective doses of japonicin A with the chemotherapeutic drug paclitaxel, decreasing cellular proliferation of the OVCAR-3 cell line. These preliminary results provide a scientific basis to further pursue these compounds as potential combined therapy for certain tumor types.

AbstractMammalian bombesin-like peptides neuromedin B (NMB) and gastrin-releasing peptide (GRP) act by activating NMB receptors (NMBR, BB1) and GRP receptors (GRPR, BB2), respectively. These two bombesin receptors are members of the G-protein-coupled receptor (GPCR) superfamily. In the brain, NMBR and GRPR are highly expressed in the brain areas involved in memory processing and emotional responses, such as the hippocampus and the amygdaloid nuclei. An increasing number of pharmacological and genetic studies in rodents indicate that NMBRs and GRPRs in brain regions including the dorsal hippocampus, the nucleus tractus solitarius, the basolateral amygdala, and cortical areas, regulate memory formation and expression, particularly for memories related to emotionally arousing tasks. GRPR signaling interacts with multiple protein kinase pathways as well as with other neurotransmitter, hormone, and growth factor systems in influencing memory formation. Together with evidence from human studies, the findings from rodent experiments suggest that bombesin receptors may be therapeutic targets in brain disorders involving memory dysfunction and anxiety.

This article will focus on basic concepts in the development of new agents for pediatric malignancies and future directions, while considering the limitations we have today and the lessons we have learned from adult cancers. In addition, basic ethical principles for conducting trials in children are summarized. The rising numbers of targeted agents that have become available over the last few years will significantly change the way clinical studies are planned and a shift towards the use of alternative end points, different selection criteria and innovative designs is necessary. Pediatric malignancies have specific particularities and disparities that distinguish them regarding the conduction and design of clinical trials, which may influence the use of novel compounds. Due to the rarity of these diseases, international groups have cooperated to increase accrual rates, and incentives to the pharmaceutical companies have been made available by regulatory authorities; however, despite this a lack of trial participation in developing countries still remains.

The present study was designed to investigate the effect of a single purple grape juice administration on cyclosporin A (CyA) oral bioavailability in healthy volunteers.

There is now compelling evidence that brain tumors harbor a small population of cells characterized by their ability to undergo self-renewal and initiate tumors, termed cancer stem cells (CSCs). The development of therapeutic strategies targeted towards CSC signaling may improve the treatment of brain tumors such as malignant gliomas and medulloblastomas. Here we review the role of cancer stem cells in glioma and medulloblastoma and some of the signaling mechanisms involved in brain tumor stem cell (BTSC) biology, and discuss how these signaling pathways may represent new stem cell targets for the treatment of brain tumors. In addition, we provide illustrative immunohistochemical data on the presence of BTSCs in human gliomas and medulloblastomas, and show preliminary findings suggesting the involvement of a GPCR, the gastrin-releasing peptide receptor (GRPR), in the expansion of BTSCs in vitro.

Cervical cancer is the second most frequent malignancy affecting women worldwide. The highest incidences occur in the developing world, where, in most countries, cervical cancer is the leading cause of cancer mortality in women. Although surgery and chemoradiotherapy can cure 80-95 of women with early stage cancer and 60 of locoregionally advanced cancer, the recurrent and metastatic disease remains a major cause of cancer death. The current cytotoxic treatment options for advanced and metastatic cancer demonstrate modest results, with response rates of maximum 30 and overall survival of less than 10 months. Given this limited degree of success with conventional therapies, interest has increased in other therapeutic alternatives. In this way, targeted agents are emerging as potential candidates for improving survival in cervical cancer patients. In this review we highlight the main current therapeutic strategies for cervical cancer and summarize the most relevant patents from the latest five years. Special attention was given to patents with potential applications in the clinical practice.

Gastrin-releasing peptide (GRP) has been proposed as a major growth factor in brain tumors, and GRP receptor (GRPR) antagonists show antiproliferative effects in experimental gliomas. However, the underlying molecular events downstream of GRPR activation remain poorly understood. In the present study, we examined the role of the GRPR in regulating proliferation of glioma cells in vitro and its possible interaction with the phosphatidylinositol 3-kinase (PI3K) signaling pathway. Expression of GRPR mRNA and protein in C6, U-87MG, and U-373MG glioma cells was analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. Proliferation of C6 and U-87MG, but not U-373MG cells was significantly inhibited by the GRPR antagonist RC-3095, whereas the GRPR agonist bombesin (BB) significantly enhanced proliferation of C6 cells. The BB-induced stimulatory effect on cell proliferation was prevented by either RC-3095 or the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. Our results provide the first evidence that the GRPR regulates proliferation of C6 glioma cells and suggest that PI3K is required for GRPR-mediated stimulation of glioma growth.

Molecular accounts of memory consolidation suggest that new learning generates persistent synaptic modifications through activation of an extensive set of neuronal receptors and intracellular signal transduction pathways, accompanied by RNA and protein synthesis. This traditional cellular consolidation theory has been challenged by evidence that reactivation of a previously consolidated memory might render this memory again susceptible to disruption by amnesic treatments, a process generally referred to as reconsolidation. Current evidence indicates that reconsolidation can be disrupted by administration of a variety of pharmacological agents after memory reactivation. Previous studies have indicated that the gastrin-releasing preferring type of bombesin receptor (GRPR) and the N-methyl-D-aspartate glutamate receptor (NMDAR) in the rat hippocampus are involved in consolidation of inhibitory avoidance (IA), a fear-related memory task. We show here that blockade of hippocampal GRPRs or NMDARs after memory reactivation temporarily disrupts memory retention. Post-retrieval intra-hippocampal infusion of the GRPR antagonist RC-3095 or the NMDAR antagonist aminophosphonopentanoic acid (AP5) produced an impairment of IA performance tested 2 days after training in rats. However, this impairment was transient and recovered to levels of control rats in a subsequent test 3 days after training. The drug effects were only present after memory reactivation and not in its absence. These findings provide evidence that GRPR or NMDAR inactivation after retrieval can impair fear memory.

Gastrin-releasing peptide (GRP) is a mammalian counterpart of the amphibian peptide bombesin (BB) that stimulates cell proliferation, acts as a growth factor in the pathogenesis of many types of cancer, and regulates several aspects of neuroendocrine function. BB and GRP act by binding to the GRP-preferring type of BB receptor (GRPR, also known as BB2 receptor), a member of the superfamily of G-protein coupled membrane receptors. This review summarizes recent evidence from animal and human studies indicating that abnormalities in GRPR function in the brain might play a role in the pathogenesis of neurological and psychiatric disorders, and suggesting that BB, GRP, and GRPR antagonists might display therapeutic actions in central nervous system diseases. Recent patent applications on GRPR-related methods for treating brain disorders are introduced.

Although the gastrin-releasing peptide receptor has been implicated in memory consolidation, previous studies have not examined whether it is involved in extinction. Here we show that gastrin-releasing peptide receptor blockade in the hippocampus disrupts extinction of aversive memory. Male rats were trained in inhibitory avoidance conditioning and then returned repeatedly to the training context without shock on a daily basis for 3 days. Infusion of a gastrin-releasing peptide receptor antagonist or the protein synthesis inhibitor anisomycin into the dorsal hippocampus immediately after the first extinction session blocked extinction. These drugs did not affect performance in subsequent sessions when the first extinction session (1 day after training) was omitted. The results indicate that hippocampal gastrin-releasing peptide receptors are involved in memory extinction.

Severe traumatic brain injury (TBI) is associated with a 35–70% mortality rate. Biochemical markers of cellular stress/injury have been proposed to indicate outcome after head injury. Therefore, our aim was to determine whether Hsp70 could be detected in the serum of patients after severe TBI and whether serum levels of Hsp70 correlate with primary outcome in severe TBI. Twenty consecutive male patients, victims of severe TBI (GCS 3–8), were enrolled in this prospective study. Clinical outcome variables of severe TBI comprised: survival, time for ICU discharge, and neurological assessment using the Glasgow Outcome Scale (GOS) at the ICU discharge. Venous blood samples were taken at admission in the ICU (study entry), 24 h later, and 7 days later. A control group consisting of eight healthy male volunteers was also included. Serum Hsp70 levels were measured by an enzyme-linked immunosorbent assay. Mean serum Hsp70 concentrations were significantly increased in the TBI (97.6, 48.1, and 39.2 ng/mL, at study entry, 24 h later, and 7 days later, respectively) compared with the control group (12.2 ng/mL). Severe TBI was associated with a 50% mortality rate. On study entry (mean time 10.8 h after injury), a higher proportion of patients with fatal outcome had elevated serum Hsp70 (mean 143.5 ng/mL) concentrations when compared with survivors (mean 51.6 ng/mL). There was a significant correlation between higher initial serum Hsp70 concentrations and fatal outcome. The sensitivity of serum Hsp70 predicting mortality according to the cutoff of 62 ng/mL is 70% within 20 h after injury. Increased serum Hsp70 levels may constitute an early predictor of unfavorable outcome in severe TBI in males.

Summary Recent research has implicated glutamate in the growth and invasive migration of gliomas. Superoxide dismutase (SOD) is involved in excitotoxicity and may influence cellular proliferative status. Thus, this study investigated the effects of gliotoxic doses of glutamate on Cu–Zn and Mn/SODs activities in human glioma cell lines. To this end, glioma cell lines (U87MG, U138MG and U251MG) were treated with glutamate (5–200?mM) during 48?h. Then, cell viability assays, clonogenic assay and Cu–Zn and Mn/SODs activities of the cell lines were performed. IC50values of glutamate were similar for both U87MG and U138MG cells (56 and 69 mM, respectively), while a higher value was detected for U251MG cells (110?mM). In the long term, 14?days after glutamate was removed from the culture media, cells showed partial or complete recovery. The effects of glutamate treatment on Cu–Zn and Mn/SODs activities varied among the distinct cell lines. While acute treatment with toxic doses of glutamate caused a significant decrease in the Cu–Zn/SOD activity of U138MG and U251MG cells, it did not affect Cu–Zn/SOD activity in U87MG cells. Only in U251MG cells, acute glutamate treatment decreased significantly Mn/SOD activity. In the long term (14?days after the 48?h treatment), glutamate did not affect either Cu–Zn or Mn/SODs activities. Thus, it may be suggested that SOD vulnerability to glutamate-mediated effects may be related to distinct tumoral cell behavior.

Extracellular purines (adenosine triphosphate (ATP), adenosine 5′-diphosphate (ADP) and adenosine) and pyrimidines (uridine 5′-triphosphate (UTP) and UDP) are important signaling molecules that mediate diverse biological effects via P1 and P2 purinergic receptors. The human glioma cell lines U87 MG, U251 MG and U138 MG were treated with purines and pyrimidines for 24 or 48h and proliferation was measured by [3H]-thymidine incorporation, flow cytometry and cell counting. The studies showed that extracellular nucleotides and nucleosides induce proliferation of the studied glioma cells. Incorporation of [3H]-thymidine followed the order of ATP ≅ guanosine ≅ inosine ≅ adenosine > UTP > ADP while ATPγS and 2MeSATP had no effect. The effect of ATP was partially inhibited by suramin and by reactive blue 2 (RB2). Co-treatment with the following antagonists of P1 purinoreceptors DPCPX, CPT or 8PT did not block the effect of adenosine while a specific antagonist of the A3receptor, MRS1220, totally blocked the effect of adenosine. ATP and adenosine also increased the overall uptake of [3H]-thymidine into the cell, producing a positive effect on the [3H]-thymidine incorporation measurements. These data indicate that the uptake of thymidine and proliferation of gliomas can be induced by purines and pyrimidines via both P1 and P2 purinoceptors.

Introduction. This study was designed to estimate the percentage of objective tumor responses, toxicity profile, and obtain additional information about the plasma pharmacokinetics of thalidomide in patients with refractory and progressing metastatic colorectal cancer. Study design. This phase II clinical trial was conducted according to the two-stage Simon method with the inclusion of consecutive patients. The study protocol was approved by the Institutional Review Board (IRB) of the Academic Hospital (HCPA) of the Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil. Patients and methods. Seventeen patients with previously treated, refractory progressive metastatic colorectal cancer were eligible. Six patients had prior radiotherapy. The patients had a median of one previous chemotherapy regimen. Patients were initially treated with 200 mg/day of thalidomide with an increase in dose by 200 mg/day every 2 weeks until a final daily dose of 800 mg/day was achieved. Patients were evaluated every 8 weeks for response by radiographic criteria. Plasma pharmacokinetics studies were performed in four patients at 200 mg level and in one patient at 600 mg during the first 24 h. Main outcome measures and results. A total of 17 patients were accrued, all of them being evaluable for toxicity and 14 for response. Thalidomide was well tolerated, with constipation, somnolence, dizziness, and dry mouth being the major toxicities. There were no objective response or stable disease. The median survival was 3.6 months. Single-agent thalidomide is a generally well-tolerated drug that showed no antitumor activity in patients with advanced pretreated metastatic colorectal cancer. Although thalidomide did not show antitumor activity in this patient population, future studies of this agent in patients at initial stages of the disease (when its antiangiogenic properties may be more relevant to disease progression) could be considered.

Anticancer agents may be derived either from the isolation of an active lead compound occurring spontaneously in nature or by novel chemical synthesis in the laboratory. There are examples of successful drugs being derived from both sources, which have had a profound impact on the natural history of various types of cancer. The treatment of lymphomas and acute leukaemias with the use of combination chemotherapy, including anthracyclines and vinca alkaloids, are examples of the contribution of nature. In contrast, agents such as 5-fluorouracil, methotrexate and more recently, the humanised anti-CD20 antibody rituximab and the tyrosine kinase inhibitor imatinib are examples of synthetic compounds, which were designed with a clear rationale, that are routinely used in patients with solid tumours and haematological malignancies. Until recently, the tradition in natural product-derived anticancer drug development was to rely almost exclusively on the screening of terrestrial sources (plant extracts and fermentation products) for their cytotoxic properties. Although C-nucleosides obtained from Caribbean sponge were the initial inspiration for the synthesis of antiviral substituted nucleosides and the successful anticancer agent citarabine, active against leukaemias and lymphomas, the contribution of marine compounds as a source of anticancer agents was modest. In recent years, the improvements in the technology of deep-sea collection and aquaculture added to the growing recognition of the tremendous biodiversity present in the marine world, and has contributed to the growing interest of exploring the oceans as a potential source of new anticancer candidates. This is reflected in the number of marine-derived compounds undergoing preclinical and early clinical development. In this paper, the authors discuss the available literature on anticancer agents that have reached clinical trials, such as didemnin B, aplidine, dolastatin-10, bryostatin-1 and ecteinascidin-743 (ET-743, trabectedin), as well as other promising compounds still undergoing tests in the laboratory.

Pleuropulmonary blastoma (PPB) is a rare and aggressive malignant tumor of the lung. Approximately 80 cases of PPB have been published, and in only three cases high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HSCT) was applied. A 5-year-old girl presenting with cough, fever, and shortness of breath was referred to the authors in March 1999. A computed tomography scan of the chest showed a tumor mass in the left hemithorax. The lesion was biopsied and the histopathologic report suggested the diagnosis of PPB. The patient received chemotherapy comprising vincristine, actinomycin D, and cyclophosphamide with only a minor response, and treatment was switched to ifosfamide, carboplatin, and etoposide, which produced a partial response. Tumor resection was performed, but margins were positive for PPB. Due to the high risk of recurrence, the authors elected to administrate high-dose chemotherapy using melphalan, etoposide, and carboplatin, followed by autologous HSCT. The patient achieved complete hematologic recovery, and reimaging after HSCT showed no evidence of disease. She relapsed 4 months later and died about 9 months after the completion of high-dose therapy. The role of high-dose chemotherapy and autologous HSCT is likely to be limited in PPB.

Various active anticancer agents are derived from plants and terrestrial microorganisms. The isolation of C-nucleosides from the Caribbean sponge, Cryptotheca crypta, four decades ago, provided the basis for the synthesis of cytarabine, the first marine-derived anticancer agent to be developed for clinical use. Cytarabine is currently used in the routine treatment of patients with leukaemia and lymphoma. Gemcitabine, one of its fluorinated derivatives, has also been approved for use in patients with pancreatic, breast, bladder, and non-small-cell lung cancer. Over the past decade, several new experimental anticancer agents derived from marine sources have entered preclinical and clinical trials. This field has expanded significantly as a result of improvements in the technology of deep-sea collection, extraction, and large-scale production through aquaculture and synthesis. In this paper, examples of marine-derived experimental agents that are currently undergoing preclinical and early clinical evaluation are briefly discussed. A summary of the available information on the results of phase I and II trials of agents such as aplidine, ecteinascidin-734 (ET-734), dolastatin 10 and bryostatin 1 is also presented.

Background In a phase II study, topotecan was evaluated for response and toxicity in patients with advanced pancreatic carcinoma at the schedule of 0.7 mg/m2/day q 21 days q 28 days.Methods Responses were assessed after at least 2 courses using WHO criteria, and toxicity was evaluated after each course according to the CTC-NCI standards. Between December 1995 and September 1997, 15 assessable patients (median age, 55 years; range, 36-74; median ECOG performance, 1; range, 0-3) were included in the study. All had biopsy-proven and measurable disease, a life-expectancy of at least 3 months, and normal bone marrow, liver, and renal function. None of the patients had undergone prior cytotoxic or radiation therapy, and 10 were initially treated by surgery. Twenty-five cycles were assessable for toxicity. Plasma was collected from 7 patients who had received a total of 10 cycles and was, after extraction with methanol at −20°C, analyzed for total topotecan by an HPLC method. The thus determined steady-state concentrations were assessed for their capacity to affect growth and DNA integrity in the BxPC-3 human pancreatic carcinoma cell line after 21 days of continuous exposure. For these purposes, we used a sulforhodamine B staining assay, and agarose gel electrophoresis, respectively.Results Grades 3-4 leukopenia, thrombocytopenia, granulocytopenia, and anemia occurred in 8, 6, 8 and 8 cycles, respectively. Other mild to moderate side effects (grades 1-2) included malaise, nausea and vomiting, anorexia, and alopecia. No objective tumor response was documented. HPLC analysis of patients' plasma showed the attainment of constant steady-state levels of 1.0 ± 0.1 ng/mL during the entire infusion period. At such a concentration, topotecan did not significantly affect growth or DNA integrity in the BxPC-3 cells. Fifty percent cell growth inhibition and appreciable oligonucleosomal DNA fragmentation were only evident with 21 days topotecan ≥ 50 ng/mL.Conclusions Our data suggest that the lack of clinical activity of 0.7 mg/m2daily topotecan for 21 days q 28 days in patients with advanced pancreatic carcinoma might be partially attributed to the achievement of non-tumoricidal plasma drug concentrations.

Throughout medical history, plant products have been shown to be valuable sources of novel anti‐cancer drugs. Examples are the Vincaalkaloids, the taxanes, and the camptothecins, derived from the Madagscan periwinkle plant Catharantus roseus, the Pacific yew Taxus brevifolia, and the Chinese tree Camptotheca acuminata, respectively. For this reason, the South‐American Office for Anti‐Cancer Drug Development has implemented a large‐scale project of acquisition and testing of compounds isolated from South American medicinal plants. The species are selected on the basis of a potentially useful phytochemical composition by consulting ethnopharmacological, chemosystemic, and ecological information. The collected samples are dried and first extracted with an organic solvent, then with distilled water. These crude extracts are evaluated at a concentration of 50 μg/ml for antiproliferative activity against one cell line. Extracts that significantly inhibit the growth of the cells (≥50%) at relatively low concentrations (≤50 μg/ml) are submitted to the more comprehensive disease‐oriented screen of the U.S. National Cancer Institute. In parallel, these samples are further purified by bioassay‐guided purification, involving repeated fractionation by diverse chromatography methods. If the active substance is expected to represent a novel structure, it is identified by appropriate chemical techniques, mechanistic studies are performed with a wide diversity of tumor models and laboratory techniques, and efforts are undertaken for the synthesis of potentially more useful analogs.

Mammalian cell shape is critically important to cell differentiation, apoptosis, cell division, and growth arrest. In the present study we examined the relationship among cell density, cell phenotype (which include shape and coupling) and cell survival using the human A549, H596 and H520 non-small cell lung carcinoma lines. Thus, cells from monolayers, aggregated and suspended cultures at different densities were exposed to UV-radiation and both the density and the phenotype of the cells induce shifts in cellular growth rate. Except in suspended cultures, we observed a UV-sensitivity closely related to the proliferative status of the cells. The variability of the cellular response to UV were investigated taking into account the shape and the coupling potential of the cell lines, suggesting that an intercellular-contact mechanism provides further protection against UV-radiation damage.

Brequinar sodium (DUP 785, NSC 368390) is a novel quinoline-carboxylic acid derivative that has been selected for clinical evaluation because of its broad spectrum of antitumor activity in animal models and its novel chemical structure. This compound inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHO-DH), which catalyzes the conversion of dihydroorotate to orotate, leading to a blockage in the pyrimidine de novo biosynthesis. A total of 43 patients received 110 courses of Brequinar sodium by short-term intravenous (i. v.) infusion, which was repeated every 3 weeks. Dose escalation was initially based on a modified Fibonacci scheme. After pharmacokinetic data from mice and man became available, a pharmacologically guided dose escalation was used; at toxic levels, dose escalation was applied on the basis of clinical judgement. The dose-limiting toxicities were myelosuppression, mucositis, skin rash, nausea and vomiting. The maximum tolerable doses for poor- and good-risk patients were 1,500 and 2,250 mg/m2, respectively. One mixed response was observed in a patient with papilary carcinoma of the thyroid. The recommended doses for phase II studies are 1,200 and 1,800 mg/m2 Brequinar sodium, given by a 1-h i.v. infusion every 3 weeks to poor- and good-risk patients, respectively.

Aims and background To evaluate the response rate, toxicity and survival of patients with AIDS-related Kaposi's sarcoma (AIDS-KS) treated in a phase II clinical trial of pentosan polysulpate (PPS), an inhibitor of basic-fibroblast growth factor (b-FGF) which blocks the growth of Kaposi's sarcoma cells both in culture and in animal models.Patients and methods Between March 1992 and March 1994 16 homosexual males with histopathologically confirmed AIDS-KS were accrued for this phase II clinical trial. PPS was administered at the dose of 25 mg/m2q6 hrs at day 1, followed by 25 mg/m2q12 hrs daily by a subcutaneous injection. The number of patients to be included in the trial was calculated according to the two-stage Gehan method. Toxicity was graded according to the NCI Common Toxicity Criteria, while responses were evaluated according to the WHO Criteria adapted for KS lesions. Patients were all homosexual males, median age 35 (27-43) years, performance status (WHO) 1 (0-2), NYU stage II-IV and prior therapy included vincristine and etoposide (3 cases), local irradiation (4 cases) and meges-trol acetate (2 cases). Concomitant AZT (zidovudine) was given to 3 patients, while DDI (dideoxyinosine) was administered in one case.Results A median of 5 (3-11) weeks of therapy was administered to the patients. Pain at the injection site and low grade fever were the only toxicities observed. Drug-related effects on coagulation parameters or thrombocytopenia were not observed in the trial. One objective response (6%) was documented, which lasted for 9 weeks, while stable disease was observed in three patients, lasting for 11, 9 and 5 weeks, respectively.Conclusion This is the first observation of objective antitumor activity with a b-FGF inhibitor in patients with AIDS-KS. Considering its novelty and the lack of significant toxicity, the authors suggest that this experimental approach deserves further evaluation.

The gastrin-releasing peptide receptor (GRPR) is a therapeutic target in colon cancer. Here we show that the GRPR antagonist RC-3095 (10-3, 10-6, or 1 M) decreases nerve growth factor (NGF) secretion measured by enzymelinked immunosorbent assay (ELISA) in HT-29 human colon carcinoma cells. The results suggest that decreased secretion of neurotrophins might be a novel mechanism by which GRPR antagonists exert their antiproliferative effects in cancer cells.