Cancer chemotherapy and pharmacology
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Cancer Chemother. Pharmacol. · Sep 2004
Clinical TrialWeekly administration of topotecan and paclitaxel in pretreated advanced cancer patients: a phase I/II study.
This study was a phase I/II, cohort, dose-escalation trial of topotecan and paclitaxel. Its aim was to determine the dose-limiting toxicity (DLT) of the combination and to define the maximum tolerated dose (MTD), as a recommended dose for phase II, as well as to get preliminary data on the efficacy (activity) of the drug in pretreated patients with ovarian cancer, small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). ⋯ Topotecan combined with paclitaxel administered once weekly for three consecutive weeks repeated for every 28 days resulted in well-tolerated toxicity at doses of 1.75 and 70 mg/m2, respectively, and a response rate of 33% in pretreated cancer patients.
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Cancer Chemother. Pharmacol. · Sep 2004
ReviewPrevention of colorectal cancer through the use of COX-2 selective inhibitors.
Colorectal cancer is a major cause of morbidity and mortality accounting for an estimated 550,000 deaths annually worldwide. Colonic neoplasia develops in a stepwise fashion progressing from normal mucosa to adenomatous polyps to carcinoma, a process that takes years, thereby providing a prime opportunity for intervention. Although early detection by fecal occult blood testing and sigmoidoscopy can decrease the risk of cancer-related death by 20-30%, most persons never undergo appropriate screening. ⋯ Recent clinical studies using specific COX-2 inhibitors have shown that these compounds can: (1) reduce intestinal polyp burden in patients with familial adenomatous polyposis; (2) prevent the occurrence and/ or recurrence of colorectal adenomas and cancers; and (3) negatively regulate angiogenesis in colorectal cancer liver metastases. Compared to nonselective NSAIDs, COX-2 specific inhibitors cause substantially fewer gastrointestinal side effects. These findings indicate that a widely used and relatively safe class of drugs may represent a viable and effective anticancer strategy for a disease that causes over a half-million deaths per year.
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Cancer Chemother. Pharmacol. · Jul 2004
Plasma and cerebrospinal fluid pharmacokinetics of depsipeptide (FR901228) in nonhuman primates.
Acetylation of histones by histone acetyl transferases (HATs) leads to transcriptional activation, while histone deacetylase (HDAC) activity leads to transcriptional repression. Abnormalities of histone acetylation are associated with the malignant phenotype. Depsipeptide (FR901228) inhibits HDAC and has shown anticancer activity in preclinical models. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics of depsipeptide in a nonhuman primate model that is highly predictive of human CSF penetration. ⋯ Although the CSF exposure to depsipeptide after intravenous administration was only 2%, CSF concentrations approached the IC(50) of depsipeptide in vitro for some tumors. Systemic administration of this agent may be useful for the treatment of leptomeningeal tumors.
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Cancer Chemother. Pharmacol. · Jun 2004
Population pharmacokinetics of melphalan, infused over a 24-hour period, in patients with advanced malignancies.
The objective of the present study was to characterize the population pharmacokinetics of melphalan infused over a 24-h period in patients with advanced malignancies. ⋯ The population pharmacokinetic approach developed in this study should allow dosage to be individualized in order to decrease toxicity while maintaining good efficacy.
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Cancer Chemother. Pharmacol. · Jun 2004
Plasma and cerebrospinal fluid pharmacokinetic study of BNP1350 in nonhuman primates.
BNP1350 (7-[(2-trimethylsilyl)ethyl]-20(S)-camptothecin, karenitecin), a highly lipophilic camptothecin, a high percentage of which is maintained in the active lactone form under physiologic conditions, has recently entered clinical trials in adults and children. BNP1350 has shown significant preclinical antitumor activity against a wide variety of adult and pediatric tumor cell lines. This study was undertaken to define the pharmacokinetics of BNP1350 in both plasma and cerebrospinal fluid (CSF) in a nonhuman primate model. ⋯ The ratio of the CSF AUC to the plasma AUC was less than 5% (range 0.4% to 3.0%), similar to other highly protein-bound topoisomerase inhibitors such as 9-aminocamptothecin and SN-38 (the active metabolite of irinotecan).