Cancer chemotherapy and pharmacology
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Cancer Chemother. Pharmacol. · Jul 2003
ReviewStrategy for the development of novel anticancer drugs.
Progress in molecular pharmacology has demonstrated each anticancer drug to have a unique molecular target. Recent drug development has focused on compounds that specifically inhibit and/or modify tumor-specific molecular biological changes (target-based drug development). These compounds are generally classified as either small molecules or macromolecules. ⋯ Parameters such as time to progression, changes in tumor markers, and growth rates often vary significantly and are regarded as soft endpoints. Phase III trials evaluating survival benefit require extensive resources, including a large number of patients, a sophisticated data center, and well-trained study groups. The problems and future prospects of novel anticancer drug development are discussed.
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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. · Jul 2003
ReviewThe opportunities and challenges of personalized genome-based molecular therapies for cancer: targets, technologies, and molecular chaperones.
There are now unprecedented opportunities for the development of improved drugs for cancer treatment. Following on from the Human Genome Project, the Cancer Genome Project and related activities will define most of the genes in the majority of common human cancers over the next 5 years. This will provide the opportunity to develop a range of drugs targeted to the precise molecular abnormalities that drive various human cancers and opens up the possibility of personalized therapies targeted to the molecular pathology and genomics of individual patients and their malignancies. ⋯ The first-in-class HSP90 inhibitor 17AAG exhibited good activity in animal models and is now showing evidence of molecular and clinical activity in ongoing clinical trials. Novel HSP90 inhibitors are also being sought. The development of HSP90 inhibitors is used to exemplify the application of new technologies in drug discovery against a novel molecular target, and in particular the need for innovative pharmacodynamic endpoints is emphasized as an essential component of hypothesis-testing clinical trials.
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Cancer Chemother. Pharmacol. · Jul 2003
Clinical TrialCombination second-line chemotherapy with gemcitabine and docetaxel for recurrent non-small-cell lung cancer after platinum-containing chemotherapy: a phase I/II trial.
In a randomized trial, docetaxel monotherapy yielded longer survival than the best supportive care in patients with non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy, and combination chemotherapy regimens containing docetaxel have been assessed to enhance the efficacy of second-line chemotherapy. We conducted a phase I/II trial of gemcitabine and docetaxel in patients with recurrent NSCLC after platinum-based chemotherapy and with an ECOG performance status (PS) of 0 or 1. ⋯ The combination chemotherapy of gemcitabine and docetaxel is active and well tolerated in patients with recurrent NSCLC after platinum-based chemotherapy and with a good PS.
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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.