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

• Published in: Cancer chemotherapy and pharmacology Vol. 58; no. 1; pp. 73 - 85
• Main Authors: ROSE, William C, MARATHE, Punit H, JANG, Graham R, MONTICELLO, Thomas M, BALASUBRAMANIAN, Balu N, LONG, Byron, FAIRCHILD, Craig R, WALL, Monroe E, WANI, Mansukh C
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.07.2006; Springer Nature B.V
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents, Phytogenic - pharmacokinetics; Antineoplastic Agents, Phytogenic - pharmacology; Biological and medical sciences; Camptothecin - analogs & derivatives; Camptothecin - chemical synthesis; Camptothecin - pharmacokinetics; Camptothecin - pharmacology; Carcinoma - drug therapy; Carcinoma - metabolism; Carcinoma - pathology; Cell Line, Tumor; Cell Survival - drug effects; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Female; Gastrointestinal Tract - drug effects; Gastrointestinal Tract - metabolism; Gastrointestinal Tract - pathology; Humans; Male; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Medical sciences; Mice; Mice, Inbred C3H; Mice, Nude; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Pharmacology. Drug treatments; Prodrugs - pharmacokinetics; Prodrugs - pharmacology; Rats; Rats, Sprague-Dawley; Tumor Burden - drug effects; Xenograft Model Antitumor Assays; Antineoplastic agent; Camptothecin; Xenograft; Toxicity; Transplantation; Gastrointestinal; Heterograft; Heterotransplantation; Gastrointestinal toxicity; Alkaloid; Isomerases; Surgery; Antitumor; Graft; Stomach; Digestive system; Enzyme; DNA topoisomerase; Gut; Enzyme inhibitor; Biological activity; In vivo; Treatment; Animal; Pharmacokinetics
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-005-0128-y

The novel fluoro-substituted camptothecin analog, BMS-286309, and its prodrug, BMS-422461, were evaluated for their pharmacologic, toxicologic, metabolic and pharmacokinetic developmental potential. In vitro and in vivo assays were used to assess the compounds for topoisomerase I activity, antitumor activity, gastrointestinal (GI) toxicity, and pharmacokinetic parameters. 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. 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.