Novel fluoro-substituted camptothecins: in vivo antitumor activity, reduced gastrointestinal toxicity and pharmacokinetic characterization.

Abstract

PURPOSE:

The novel fluoro-substituted camptothecin analog, BMS-286309, and its prodrug, BMS-422461, were evaluated for their pharmacologic, toxicologic, metabolic and pharmacokinetic developmental potential.

METHODS:

In vitro and in vivo assays were used to assess the compounds for topoisomerase I activity, antitumor activity, gastrointestinal (GI) toxicity, and pharmacokinetic parameters.

RESULTS:

BMS-286309-induced topoisomerase I-mediated DNA breaks in vitro and was similar in potency to camptothecin. Both BMS-286309 and -422461 were comparable to irinotecan regarding preclinical antitumor activity assessed in mice bearing distal site murine and human tumors. BMS-422461 was also found to be orally active. Both analogs were >100-fold more potent in vivo than irinotecan and both were superior to irinotecan with respect to toxicological assessment of GI injury in mice. The generation of parent compound from BMS-422461 was qualitatively similar in mouse, rat and human blood and liver S9 fractions. The percentage of BMS-286309 remaining as the active lactone form at equilibrium was comparable in mouse and human plasma. The pharmacokinetic profile in rat blood demonstrated that BMS-422461 was rapidly cleaved to BMS-286309.

CONCLUSIONS:

The favorable in vivo metabolic activation of BMS-422461, and the pharmacokinetic characteristics of BMS-286309, suggest that the good efficacy of BMS-422461 is derived from robust in vivo release of BMS-286309 in rodents and the likelihood that this biotransformation will be preserved in humans. The comparable antitumor activity of BMS-422461 to irinotecan, as well as reduced preclinical GI toxicity, make this novel camptothecin analog attractive for clinical development.

• Authors: William C Rose, Punit H Marathe, Graham R Jang, Thomas M Monticello, Balu N Balasubramanian, Byron Long, Craig R Fairchild, Monroe E Wall, Mansukh C Wani
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 58 Issue 1 Pg. 73-85 (Jul 2006) ISSN: 0344-5704 [Print] Germany
• PMID: 16228206 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents, Phytogenic
• BMS 286309
• BMS 422461
• Prodrugs
• Irinotecan
• Camptothecin

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacokinetics, pharmacology)
• Camptothecin (analogs & derivatives, chemical synthesis, pharmacokinetics, pharmacology)
• Carcinoma (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Colonic Neoplasms (drug therapy, metabolism, pathology)
• Female
• Gastrointestinal Tract (drug effects, metabolism, pathology)
• Humans
• Irinotecan
• Male
• Mammary Neoplasms, Experimental (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred C3H
• Mice, Nude
• Ovarian Neoplasms (drug therapy, metabolism, pathology)
• Prodrugs (pharmacokinetics, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays