Homocamptothecins: E-ring modified CPT analogues.
Homocamptothecins (hCPT) are modified camptothecins (CPT) with a seven-membered beta-hydroxylactone instead of the naturally occurring six-membered alpha-hydroxylactone. This E-ring modification fully conserves the ability to stabilize topo I-DNA single-strand breaks and stimulates high levels of DNA cleavage. A key feature is the irreversibility of E-ring opening, which should give reduced toxicity. Substituted hCPTs have been selected for their high antiproliferative activity on a panel of tumor cell lines, including those with cross resistance, and were found to be active at very low doses in a variety of human tumor xenografts when administered orally. BN 80915, a difluoro-hCPT, has entered clinical trials.
Lavergne
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Institut Henri Beaufour, 5 avenue du Canada, 91966 Les Ulis, France. olivier.lavergne@beaufour-ipsen.com
Demarquay
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Kasprzyk
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Bigg
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D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C120029:homocamptothecin; D002166:Camptothecin