title: Novel fluoro-substituted camptothecins: in vivo antitumor activity, reduced gastrointestinal toxicity and pharmacokinetic characterization.
abstract: OBJECTIVE
  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.affiliation: Pharmaceutical Research Institute, Bristol-Myers Squibb Co., Inc., Lawrenceville, NJ, USA. rosew@bms.com
authors.forename: William C
authors.initials: WC
authors.lastname: Rose
authors.forename: Punit H
authors.initials: PH
authors.lastname: Marathe
authors.forename: Graham R
authors.initials: GR
authors.lastname: Jang
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Monticello
authors.forename: Balu N
authors.initials: BN
authors.lastname: Balasubramanian
authors.forename: Byron
authors.initials: B
authors.lastname: Long
authors.forename: Craig R
authors.initials: CR
authors.lastname: Fairchild
authors.forename: Monroe E
authors.initials: ME
authors.lastname: Wall
authors.forename: Mansukh C
authors.initials: MC
authors.lastname: Wani
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C511490:BMS 286309; C511491:BMS 422461; D011355:Prodrugs; D000077146:Irinotecan; D002166:Camptothecin