Cancer chemotherapy and pharmacology
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Cancer Chemother. Pharmacol. · Jul 2003
Historical ArticleAnticancer drug development at the US National Cancer Institute.
Anticancer drug discovery and development is a rapidly evolving field. Recent advances in molecular oncology and the effort to completely sequence the human genome has led to an explosion in our understanding of the mechanisms involved in the transformation and growth of malignant cells. ⋯ This review summarizes the history of drug screening and development efforts at the NCI over the past five decades from its inception up to its current state emphasizing molecularly targeted therapies. These changes have not only had an impact on drug discovery, but they are also providing new paradigms for the design and conduct of preclinical and early clinical trials.
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Cancer Chemother. Pharmacol. · Jul 2003
ReviewMonoclonal antibodies for the treatment of hematologic malignancies: clinical trials in Japan.
Of 12 patients with relapsed CD20(+) B-cell non-Hodgkin's lymphoma (B-NHL) enrolled in a phase I study of rituximab, 11 were eligible, and of these 2 achieved a complete response and 5 a partial response. The elimination half-life of rituximab was 445+/-361 h, and serum rituximab levels were detectable at 3 months. In a phase II study, 90 patients with relapsed indolent B-NHL or mantle cell lymphoma (MCL) were treated with infusions of rituximab 375 mg/m(2) once weekly for four doses. ⋯ Gemtuzumab ozogamicin (CMA-676) is a calicheamicin-conjugated humanized anti-CD33 monoclonal antibody. Of 20 patients with relapsed or refractory acute myeloid leukemia enrolled in a "bridging" phase I/II study, 7 showed an objective response. It is concluded that monoclonal antibodies will have play a significant role in the treatment of hematologic malignancies in the future.
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Cancer Chemother. Pharmacol. · Jun 2003
Single-dose pharmacokinetics of the DNA-binding bioreductive agent NLCQ-1 (NSC 709257) in CD2F1 mice.
NLCQ-1 (NSC 709257) is a weak DNA-binding bioreductive antiproliferative agent, with potent in vitro antiproliferative activity against rodent and human tumor cell lines under aerobic and anaerobic conditions. Interest in this quinoline analog is based in part on its in vivo synergistic antitumor effect with radiotherapy or chemotherapy against mouse tumors and human xenografts. A sensitive, specific HPLC method was developed to measure NLCQ-1 in biological fluids. ⋯ NLCQ-1 had high (85%) intraperitoneal and modest (28%) oral relative bioavailability. Little of the administered NLCQ-1 dose (6.4%) was excreted in 24-h urine. The mouse pharmacokinetic data suggested that oral administration may achieve plasma concentration and systemic exposure similar to those observed after intravenous administration of NLCQ-1.
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Cancer Chemother. Pharmacol. · May 2003
Clinical TrialA phase II and pharmacokinetic study of pegylated liposomal doxorubicin in patients with advanced hepatocellular carcinoma.
Chemotherapy of advanced hepatocellular carcinoma (HCC) is frequently limited by unacceptable toxicity. Long-circulating polyethylene glycol-coated (PEGylated) liposomal doxorubicin (PLD) has low systemic toxicity. Its safety and efficacy in patients with advanced HCC and the relationship between hepatic function and pharmacokinetics were investigated in this phase II study. ⋯ The disposition of PLD in patients with liver dysfunction was not hampered, but it did not exhibit higher activity compared with free drug, and the risk of infection must be watched closely especially in patients with liver cirrhosis.
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Cancer Chemother. Pharmacol. · Mar 2003
Case ReportsResponse to imatinib mesylate of a gastrointestinal stromal tumor with very low expression of KIT.
More than 90% of gastrointestinal stromal tumors (GISTs) express the receptor tyrosine kinase KIT, and activating mutations of the KIT gene are detectable in the vast majority of these tumors. Imatinib mesylate (formerly STI571) is a potent inhibitor of KIT kinase activity and has been proven to be highly active in patients with unresectable or metastatic GIST expressing immunohistochemically detectable KIT protein. ⋯ The tumor was morphologically typical for a GIST, stained positively for CD34, and harbored an in-frame deletion (WK 557-558) in KIT exon 11 that is common in GISTs. Our experience with this patient suggests that even GISTs with very low levels of KIT expression may respond to imatinib mesylate therapy.