Camptothecin

Dose-escalation study was performed to evaluate the maximum tolerated dose, recommended dose and toxicity profile of weekly irinotecan with daily carboplatin and concurrent thoracic radiotherapy in patients with locally advanced non-small-cell lung cancer. Thirty-one previously untreated patients with unresectable stage III non-small-cell lung cancer were enrolled in this study. Patients received weekly irinotecan plus carboplatin (20 mg x m(-2) daily for 5 days a week) for 4 weeks and thoracic radiotherapy (60 Gy in 30 fractions). The irinotecan dose was escalated from 30 mg x m(-2) in increments of 10 mg x m(-2). Four irinotecan dose levels were given and 30 patients were assessable. Their median age was 62 years (range: 52-72 years), 28 had a performance status of 0-1 and two had a performance status of 2, 12 had stage IIIA disease and 18 had IIIB disease. There were 19 squamous cell carcinomas, 10 adenocarcinomas, and one large cell carcinoma. The dose-limiting toxicities were p...

The purpose of this study was to assess the feasibility of administering exatecan, a water-soluble, potent camptothecin analogue, as a protracted 21-day continuous i.v. infusion (CIVI). The study also sought to determine the maximum tolerated dose (MTD) of exatecan on a 21-day CIVI schedule, characterize its pharmacokinetic behavior, and seek preliminary evidence of anticancer activity. Experimental Design: Exatecan dose-schedule development was performed in two stages using the modified Continual Reassessment Method and single patient cohorts. First, patients with advanced solid malignancies were treated with exatecan (0.15 mg/m(2)/day) as a CIVI for 5 days, and the duration of the CIVI was incrementally increased from 5 to 21 days. In the second stage of the study, the dose was incrementally increased to derive a tolerable dose of exatecan administered as 21-day CIVI. The MTD was defined for both minimally pretreated (MP) and heavily pretreated (HP) patients as the highest dose le...

Withanolides are a group of pharmacologically active compounds present in most prodigal amounts in roots and leaves of Withania somnifera (Indian ginseng), one of the most important medicinal plants of Indian traditional practice of medicine. Withanolides are steroidal lactones (highly oxygenated C-28 phytochemicals) and have been reported to exhibit immunomodulatory, anticancer and other activities. In the present study, a quantitative structure activity relationship (QSAR) model was developed by a forward stepwise multiple linear regression method to predict the activity of withanolide analogs against human breast cancer. The most effective QSAR model for anticancer activity against the SK-Br-3 cell showed the best correlation with activity (r(2)=0.93 and rCV(2) =0.90). Similarly, cross-validation regression coefficient (rCV(2)=0.85) of the best QSAR model against the MCF7/BUS cells showed a high correlation (r(2)=0.91). In particular, compounds CID_73621, CID_435144, CID_301751 a...

P.108. UPDATED RESULTS OF A PHASE II TRIAL OF BEVACIZUMAB AND IRINOTECAN IN RELAPSED HIGH-GRADE GLIOMA
V. F. Keyrouz 1, E. Elias 1, G. Y. Chahine 1,2, Y. G. Comair 3, H. Dimassi 4, and F. G. Kamar 1,5; 1CHU Notre Dame des Secours – Universite ́ Saint Esprit Kaslik, Byblos, Lebanon; 2CHU Hotel Dieu De France – Universite ́ Saint Joseph, Beirut, Lebanon; 3Baylor College of Medicine, Houston, TX, United States; 4Lebanese American University, Beirut, Lebanon; 5Clemenceau Medical Center – Johns Hopkins International, Beirut, Lebanon
BACKGROUND: Relapsed glioblastoma multiforme (GBM) has a poor response to current chemotherapy and prognosis of patients with recurrent disease is dismal, with a median survival of 3–6 months. Numeral trials using bevacizumab, a humanized IgG1 monoclonal antibody to vascular endothelial growth factor (VEGF), with or without chemotherapy, have reported excellent response rates using 10 mg/kg or 15 mg/kg every 2 weeks, and allowed expedite FDA approval for its use as a second-line treat- ment in relapsed GBM. We performed a phase II trial of bevacizumab using 5 mg/kg only, with irinotecan (CPT 11) every 2 weeks as reported in the initial presentation by Stark Vance. In our interim analysis, we had demon- strated excellent response rates and similar results to others. This is an update of the final results. PATIENTS AND METHODS: This phase II trial accrued 30 patients with recurrent GBM who received bevacizumab at 5 mg/kg and CPT 11 at 125 mg/m2 every 2 weeks, after failing radiation therapy and adjuvant TMZ. All patients on antiepileptic drugs (AEDs) had their regimen changed to nonenzyme-inducing antiepileptic drugs (NEIAEDs) prior to receiving CPT 11. Patients with KPS ≥50% were allowed regardless of prior relapses. Patients were evaluated clinically and with contrast-enhanced MRI scan every 4 treatments of bevacizumab until pro- gression. RESULTS: All 30 patients were evaluable. Responses were assessed radiographically according to the MacDonald criteria and comparing T2 or Flair weighed Sequences; 19 patients (63%) had a documented response (CR + PR), 6 patients (20%) had stable disease (SD) and 5 patients (19%) progressed (PD). The average number of bevacizumab treatments received was 5.6 (1 – 20). The 6-month progression-free survival was 33.4%; 6-month overall survival was 66.7%, median overall survival was 8.7 months (36.3 weeks); median progression-free survival was 5 months (22.8 weeks). Several complications were reported: 3 DVTs and 2 PEs requir- ing IVC filter placement, 2 intracranial hemorrhages and one nonneurosur- gical complication. All patients had a clinical benefit and were taken off steroids rapidly after starting bevacizumab regardless of radiological response. Clinical and radiographic responses correlated well. Failures were mostly local progression in 12 cases, infiltrative nonenhancing (glioma- tosis like) in 10 cases and multifocal including subependymal and leptome- ningeal in 8 patients. CONCLUSION: Bevacizumab-based regimen for relapsed GBM demonstrates superior activity when compared with historical treatments. It is safe and improves overall quality of life in this patients’ cat- egory. Our results were as attractive as previously reported series despite lower KPS on enrollment, and using lower doses of bevacizumab.

The review provides a detailed discussion of recent advances in the medicinal chemistry of
camptothecin, a potent antitumor agent that targets topoisomerase I. Thousands of CPT derivatives have been
synthesized. Two of them, Topotecan and Irinotecan, are commercially approved for use in clinic as antitumor
agents while more are still in clinic trials. This review summarizes the current status of the modern synthetic
approaches to CPT, the mechanism of action of CPT, the structure-activity relationship(SAR), a number of
novel CPT analogs and their biologic activity. There is a systematic evaluation of A-, B- and E-ring- modified
camptothecins reported recently.

The profitable production of some important plant-based secondary metabolites (ginsenosides, saponins, camptothecin, shikonins etc.) in vitro by gamma irradiation is a current area of interest. We reviewed different types of secondary metabolites, their mode of synthesis and effect of γ-radiation on their yield for different plants, organs and in vitro cultures (callus, suspension, hairy root). Special effort has been made to review the biochemical mechanisms underlying the increase in secondary metabolites. A comparison of yield improvement with biotic and abiotic stresses was made.

Introduction: Besides clinicopathological parameters, molecular markers can be very important, and further characterize colorectal carcinomas into chromosomally unstable, microsatellite instable and “CqG-island methylator phenotype” groups. Aim: To study the frequency of microsatellite instability using immunohistochemical evaluation of MLH1, MSH2, MSH6 and PMS2 proteins in colorectal carcinoma. Method: 122 colorectal carcinomas as well as in 69 paired liver metastases were evaluated. Additionally, prognostic and predictive potential of mismatch repair status was tested. Results: Microsatellite instable phenotype was identified in 11.5% (14/122) of the tumours. There were no differences regarding staining intensity of tumour regions. Mismatch repair status was discordant in primaries vs. metastases in 20.2%. There was no difference in progression free- and overall survival according to mismatch repair status. The mismatch repair status was not predictive for survival within systemic...

Capecitabine has been developed as a prodrug of FU, with the goal of improving tolerability and intratumor drug concentration through tumor-specific conversion to the active drug. The purpose of this article is to review the available information on capecitabine with respect to clinical efficacy for tumors of the digestive tract, adverse-effect profile, documented drug interactions, dosage and administration, and future directions of ongoing research. Relevant English-language literature was identified through searches of NCI, PubMed, ASCO.org and ESMO, ECCO meetings proceedings.

Patients generally die of cancer after the failure of current therapies to eliminate residual disease. A subpopulation of tumor cells, termed cancer stem cells (CSC), appears uniquely able to fuel the growth of phenotypically and histologically diverse tumors. It has been ...

Current systemic treatment options for patientswith relapsed gliomas are limited. Thetopoisomerase I inhibitor topotecan has demonstrated broadantitumor activity in both preclinicalstudies as well as a number of phase I and II trials in humans.Studies in primates have shown goodcerebrospinal fluid levels of topotecan following systemicadministration. We therefore performed this phase II trial in patients who developed evidence of progressive glioma after definitive radiation therapy. Patients were treated with 1.5mg/m2 intravenously daily for 5 consecutive days repeatedevery three weeks. For patients who had received priornitrosourea-containing chemotherapy, thestarting dose was 1.25 mg/m2. Thirty-three patients wereentered on this study. All patients wereeligible and evaluable for both response and toxicity. Sevenpatients experienced grade 4 leukopeniawith 2 of these patients dying of infection-relatedcomplications. Six of these seven patients werenot taking anticonvulsants during treatment. Nine patientsdeveloped grade 3-4 thrombocytopenia,seven of whom were not taking anticonvulsants. Nonhematologicside effects were infrequent andmanageable. One patient experienced a partial response to thistreatment for an overall response rateof 3% (95% binomial confidence interval 0.3%-20.4%). The median time to progression was 14.9weeks and median survival 19.9 weeks. Topotecan at this dose andschedule showed no substantial activity in relapsed gliomas.

Colorectal cancer (CRC) is common in North America. Metastatic disease is present at diagnosis in 30% of the patients, and approximately half of early-stage patients will eventually present with metastatic disease. Until recently, few chemotherapy options were available to treat metastatic CRC. The authors review the results of recent clinical trials and the design of ongoing trials in the management of patients with metastatic colorectal cancer. Fluorouracil (5-FU) with leucovorin (LV) modulation has a marginal but positive effect on survival in those patients. The recent incorporation of irinotecan (CPT-11) and oxaliplatin for the management of advanced CRC has generated further improvement in survival. The development of oral fluoropyrimidines, mimicking continuous infusion 5-FU, is convenient. In randomized trials, capecitabine was equally effective to bolus 5-FU and LV in the management of metastatic CRC. Recently completed or ongoing clinical trials to study novel targeting ag...

Chemotherapy has had limited success in the treatment of cancer over the years, due, in part, to the untoward toxicity of the therapeutic agent to normal cells. The design of tailor-made polymer conjugates provides a synthetic approach that can overcome some of the problems. Several synthetic polymer-based anticancer drug conjugates have entered clinical studies. This report reviews the chemistry, physicochemical properties, and therapeutic applications in cancer therapy of polymeric chemotherapeutic agents based on poly(L-glutamic acid). Targeted delivery of anticancer agents using poly(L-glutamic acid) as the drug carrier is also discussed with emphasis on the design of innovative polymeric constructs.

CPT13 is a novel semi-synthetic analogue of camptothecin, it successfully overcomes the poor water solubility of the parent drug. Our previous report had shown that it exhibited good anti-tumor activity. In the present study, as a part of safety evaluation, the subacute toxicity of CPT13 was investigated. The test chemical was administered intravenously at dose levels of 0, 0.005, 0.021, and 0.085mg/kg/day for 4 weeks to male and female rats. During the test period, clinical signs, body weights, food consumption, urinalysis, hematology, serum biochemistry, organ weights, and histopathology were examined. In both sexes of the high dose group, a reduction in the body weight gain and food consumption , an increase in the incidence of abnormal clinical signs were observed. Hematological investigations revealed an increase in red blood cells (RBC) and platelets in females and a decrease in the white blood cells (WBC) in both sexes. No treatment-related adverse effects were observed in both sexes of the low and middle dose groups. Histopathological alterations included an increase in the incidence of hydropic degeneration in renal tubular epithelial cells, slight shrink in hepatocyte, and subcutaneous edema in livers. From these results, the target organs of CPT13 were determined to be kidney, liver and blood cells. The majority of those toxicity manifestations are reversible at the end of 2-week recovery period. So in the present experimental conditions, CPT13 is safe enough to be used as an alternative drug to cancer therapy.

Purpose In previous research, we found that 10-methoxy-9-nitrocamptothecin (MONCPT) possessed potent anti-tumor activity in A549 cells in vitro and in vivo. In this paper, our purpose is to investigate the mechanism of MONCPT-induced cell cycle arrest in A549 cells. Methods Cell cycle distribution was measured using flow cytometry (FCM). Protein expression and RNA expression were analyzed by western blotting and real-time PCR, respectively. SiRNA technology was introduced to silence the expression of p53 and p38. Results FCM showed that MONCPT induced cell cycle G2/M arrest in time- and dose-dependent manner. The levels of feedback loop proteins PLK-1, Cdc25C, and cyclinB1 were obviously increased from 12 to 24 h, and then reduced from 36 to 48 h by MONCPT (100.0 nM). Moreover, down-regulation of p-AKT in A549 cells was seen after treated with 100.0 nM MONCPT for 12–48 h. Over-expression of p53 and p21 in A549 cells treated with MONCPT was observed in time-dependent manner. When wild type p53 expression was specifically inhibited by RNA-interference, A549 cells treated with MONCPT delayed the onset of G2/M arrest; meanwhile p-ERK and Cdc2 were up-regulated while p21 and CDK7 were down-regulated in A549 cells treated with MONCPT and p53 SiRNA transfection in contrast to cells treated with 100.0 nM MONCPT alone. In addition, our results exhibited that MONCPT obviously down-regulated p-ERK, JNK, p-JNK, and p-p38. Treatment with p38 mitogen-activated protein kinase (MAPK) SiRNA obviously inhibited p38 MAPK and delayed the G2/M arrest induced by 50.0 nM MONCPT after 48 h. Conclusion Cell cycle regulators, AKT, p53, and MAPK, as therapeutic targets for MONCPT to induce cell cycle G2/M arrest in the context of anticancer therapy.