TY - JOUR
T1 - The current status of camptothecin analogues as antitumor agents
AU - Slichenmyer, William J.
AU - Rowinsky, Eric K.
AU - Donehower, Ross C.
AU - Kaufmann, Scott H.
N1 - Funding Information:
The European Organization for Research and Treatment of Cancer (EORTC) and the U.S. National Cancer Institute (NCI) are offering an exchange program to enable cancer researchers to work at NCI or EORTC-related institutions for one to three years.
PY - 1993/2/17
Y1 - 1993/2/17
N2 - The nuclear enzyme topoisomerase I (topo I) has been recently recognized as the target for the anticancer drug camptothecin (CPT) and its derivatives. Two of the agents that target this enzyme-topotecan (TPT) and CPT-11-appear to be active against a broad range of human tumors. In the following presentation, we review 1) the role of topo I in normal cells, 2) the chemistry and proposed mechanism of action of CPT and its analogues, 3) the results of preclinical and clinical testing of TPT and CPT-11, and 4) mechanisms of resistance to these agents. In normal cells, topo I is thought to be involved in gene transcription and DNA replication. During the course of its normal catalytic cycle, topo I transiently forms a covalent bond with DNA. CPT and its derivatives slow the religation step of the enzyme and stabilize the covalent adduct between topo I and DNA. In S-phase cells, advancing replication forks convert these topo I-DNA adducts into double-strand breaks that appear to be responsible for the cytotoxicity of these agents. Preclinical studies demonstrate antineoplastic activity for TPT and CPT-11 in a variety of tumor models. Phase I studies have identified neutropenia as the dose-limiting toxicity for both drugs. Gastrointestinal effects might also be dose-limiting for CPT-11 administered on some schedules. CPT-11 has shown antitumor activity in phase II trials for patients with carcinomas of lung, cervix, ovary, colon, and rectum and for patients with non-Hodgkin's lymphoma. Phase II studies of TPT are in progress. Resistance to the cytotoxic effects of these agents might result from decreased production of topo I or from production of a mutated form of topo I. In addition, decreased metabolic activation of CPT-11 (which is a pro-drug) and active efflux of TPT by P-glycoprotein-mediated transport might contribute to resistance. As agents with a novel mechanism of action, tolerable toxicity, and encouraging antitumor activity in early clinical trials, TPT and CPT-11 are undergoing further clinical development. If these agents can be successfully combined with other active chemotherapy agents, the topo I-directed agents offer the potential for significant advances in the treatment of patients with a variety of malignancies. [J Natl Cancer Inst 85: 271-291, 1993].
AB - The nuclear enzyme topoisomerase I (topo I) has been recently recognized as the target for the anticancer drug camptothecin (CPT) and its derivatives. Two of the agents that target this enzyme-topotecan (TPT) and CPT-11-appear to be active against a broad range of human tumors. In the following presentation, we review 1) the role of topo I in normal cells, 2) the chemistry and proposed mechanism of action of CPT and its analogues, 3) the results of preclinical and clinical testing of TPT and CPT-11, and 4) mechanisms of resistance to these agents. In normal cells, topo I is thought to be involved in gene transcription and DNA replication. During the course of its normal catalytic cycle, topo I transiently forms a covalent bond with DNA. CPT and its derivatives slow the religation step of the enzyme and stabilize the covalent adduct between topo I and DNA. In S-phase cells, advancing replication forks convert these topo I-DNA adducts into double-strand breaks that appear to be responsible for the cytotoxicity of these agents. Preclinical studies demonstrate antineoplastic activity for TPT and CPT-11 in a variety of tumor models. Phase I studies have identified neutropenia as the dose-limiting toxicity for both drugs. Gastrointestinal effects might also be dose-limiting for CPT-11 administered on some schedules. CPT-11 has shown antitumor activity in phase II trials for patients with carcinomas of lung, cervix, ovary, colon, and rectum and for patients with non-Hodgkin's lymphoma. Phase II studies of TPT are in progress. Resistance to the cytotoxic effects of these agents might result from decreased production of topo I or from production of a mutated form of topo I. In addition, decreased metabolic activation of CPT-11 (which is a pro-drug) and active efflux of TPT by P-glycoprotein-mediated transport might contribute to resistance. As agents with a novel mechanism of action, tolerable toxicity, and encouraging antitumor activity in early clinical trials, TPT and CPT-11 are undergoing further clinical development. If these agents can be successfully combined with other active chemotherapy agents, the topo I-directed agents offer the potential for significant advances in the treatment of patients with a variety of malignancies. [J Natl Cancer Inst 85: 271-291, 1993].
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U2 - 10.1093/jnci/85.4.271
DO - 10.1093/jnci/85.4.271
M3 - Review article
C2 - 8381186
AN - SCOPUS:0027447420
SN - 0027-8874
VL - 85
SP - 271
EP - 291
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 4
ER -