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Homocamptothecins: E-ring modified CPT analogues.
O Lavergne1, D Demarquay, P G Kasprzyk
1Institut Henri Beaufour, 5 avenue du Canada, 91966 Les Ulis, France. olivier.lavergne@beaufour-ipsen.com
Annals of the New York Academy of Sciences
|February 24, 2001
Summary
Homocamptothecins (hCPT) offer improved cancer treatment by stabilizing DNA breaks with reduced toxicity. These modified camptothecins show potent anti-tumor activity in preclinical models and are advancing to clinical trials.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Pharmacology
Background:
- Camptothecins (CPT) are potent anticancer agents that inhibit topoisomerase I (topo I).
- Naturally occurring CPTs possess a six-membered alpha-hydroxylactone E-ring, which is prone to hydrolysis, leading to toxicity.
- Homocamptothecins (hCPT) feature a modified seven-membered beta-hydroxylactone E-ring, aiming to improve stability and reduce toxicity.
Purpose of the Study:
- To evaluate the efficacy and safety profile of novel homocamptothecins (hCPTs) as anticancer agents.
- To investigate the mechanism of action and antiproliferative activity of hCPTs against various cancer cell lines.
- To assess the in vivo efficacy of hCPTs in human tumor xenograft models.
Main Methods:
- Synthesis and chemical modification of camptothecin analogs to create homocamptothecins.
- In vitro evaluation of antiproliferative activity against a panel of human tumor cell lines, including drug-resistant lines.
- In vivo studies using human tumor xenografts in mice to assess oral bioavailability and antitumor efficacy.
- Assessment of topoisomerase I inhibition and DNA cleavage activity.
Main Results:
- Homocamptothecins (hCPTs) demonstrated potent stabilization of topoisomerase I-DNA single-strand breaks, stimulating high levels of DNA cleavage.
- The modified beta-hydroxylactone E-ring in hCPTs showed irreversible opening, suggesting a potential for reduced toxicity.
- Substituted hCPTs exhibited significant antiproliferative activity against diverse tumor cell lines, including those with cross-resistance.
- hCPTs were effective at very low doses in various human tumor xenografts following oral administration.
- BN 80915, a difluoro-hCPT, has progressed to clinical trials.
Conclusions:
- Homocamptothecins represent a promising class of anticancer agents with enhanced efficacy and potentially reduced toxicity compared to traditional camptothecins.
- The structural modification of the E-ring in hCPTs is crucial for their potent antitumor activity and favorable pharmacokinetic properties.
- Further clinical investigation of hCPTs, such as BN 80915, is warranted for the treatment of various cancers.