Preclinical evaluation of CPT-11 and its active metabolite SN-38.
CPT-11 (irinotecan) is a water-soluble analogue of camptothecin (CPT), an antitumor drug extracted from the Chinese tree Camptotheca acuminata. SN-38 is an active metabolite of CPT-11 that contributes significantly to its activity. The antitumor effects of CPT-11 and SN-38 are exerted through a novel mechanism of action; inhibition of DNA topoisomerase I. CPT-11 and its metabolite have demonstrated potent inhibitory activity against a variety of cancer cell lines in vitro and against several murine and human tumors grafted in mice in vivo, including those that express multidrug resistance. CPT-11 has also shown synergistic activity in combination with 5-fluorouracil and cisplatin in vitro. No irreversible or unusual toxicities were observed with CPT-11 in animal toxicity studies. In summary, the preclinical profile of CPT-11 confirmed this drug to be an attractive candidate for clinical development.
Lavelle
F
F
Rhône-Poulenc Rorer R&D, Centre de Recherche de Vitry-Alfortville, Vitry-sur-Seine, France.
Bissery
M C
MC
André
S
S
Roquet
F
F
Riou
J F
JF
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D004249:DNA Damage; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D000077146:Irinotecan; D009374:Neoplasms, Experimental / Q000188:drug therapy; D059004:Topoisomerase I Inhibitors
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D002166:Camptothecin