Irinotecan (CPT-11): a brief overview.
1. Irinotecan (also known as CPT-11) is a water soluble, semi-synthetic analogue of 20(S)camptothecin (CPT) with promising activity against a range of tumour types. 2. As with all other active analogues of CPT, irinotecan causes cell toxicity by stabilizing a ternary complex between the nuclear enzyme topoisomerase I (topo I) and double-stranded DNA. This leads to replication fork-arrest, double DNA strand breaks and, possibly, illegitimate recombination of vital genes. 3. This activity is much greater for its metabolite SN-38 and irinotecan is widely considered to be a prodrug of SN-38. 4. The anti-topo I activity of CPT is stereoselective at C-20 and irinotecan is synthesized from 20(S)CPT to ensure maximal activity. In aqueous solutions, the lactone ring of CPT undergoes reversible and spontaneous hydrolysis to a ring-opened and inactive carboxylate form. In patients, it has been shown that the lactone is the predominant form of SN-38 in plasma, whereas the opposite is true for irinotecan. 5. The transformation of irinotecan to SN-38 is catalysed by carboxylesterases. However, this conversion appears relatively inefficient in man. 6. Irinotecan and SN-38 show evidence of other metabolic reactions (type I and II), some of which could be subject to pharmacogenetic variability. 7. Therapy with irinotecan is associated with unusual toxicities, such as an acute cholinergic-like syndrome and delayed onset diarrhoea. Although the mechanism for the diarrhoea remains to be defined, the cholinergic toxicity appears to be due to an inhibition of acetylcholinesterase.
University of Queensland, Department of Medicine, Princess Alexandra Hospital, Woolloongabba, Australia.
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D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D000077146:Irinotecan; D013329:Structure-Activity Relationship
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D000077146:Irinotecan; D002166:Camptothecin