title: Pharmacokinetics and antitumor efficacy of XMT-1001, a novel, polymeric topoisomerase I inhibitor, in mice bearing HT-29 human colon carcinoma xenografts.
abstract: OBJECTIVE
  To evaluate the pharmacokinetics and tissue disposition of macromolecular camptothecin (CPT) drug conjugate, XMT-1001, and irinotecan (CPT-11) in mice bearing HT-29 xenograft tumors.
  
  
  METHODS
  The antitumor efficacy of XMT-1001 was evaluated in the mouse HT-29 human colon carcinoma xenograft model. XMT-1001 was administered intravenously to female athymic nude (nu/nu) mice bearing established HT-29 xenograft tumors (n = 10) at 15, 30, and 60 mg CPT equivalents/kg on weekly or biweekly schedules. The tumor growth inhibition and tumor growth delay endpoints were used for efficacy evaluation. In the pharmacokinetic study, XMT-1001 was administered intravenously at a pharmacologically relevant dose of 60 mg CPT equivalents/kg × 1 via tail vein or an equimolar dose of CPT-11 at 100 mg/kg i.p. × 1. Mice (n = 3 per time point) were euthanized from 0.083 to 336 hours after XMT-1001 administration and from 0.083 to 24 hours after CPT-11. Plasma, tumor, and tissues were collected from all animals. A liquid chromatography-tandem mass spectrometry assay was used to measure XMT-1001, conjugate release products, CPT-20-O-(N-succinimido-glycinate; CPT-SI) and CPT-20-O-(N-succinamidoyl-glycinate; CPT-SA), and CPT.
  
  
  RESULTS
  After XMT-1001 administration, the majority of the plasma exposure is accounted for by conjugated CPT. XMT-1001 exhibited a prolonged exposure of conjugated drug, active conjugate primary release products, CPT-SI and CPT-SA, and active CPT, which was associated with greater antitumor response compared with CPT-11.
  
  
  CONCLUSIONS
  XMT-1001 provides an extended systemic and tumor exposure of conjugated drug and shows improved antitumor effect compared with CPT-11.
authors.affiliation: Division of Pharmacotherapy & Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Walsh
authors.forename: Suzan K
authors.initials: SK
authors.lastname: Hanna
authors.forename: Jeremy
authors.initials: J
authors.lastname: Sen
authors.forename: Sumit
authors.initials: S
authors.lastname: Rawal
authors.forename: Carolina B
authors.initials: CB
authors.lastname: Cabral
authors.forename: Alex V
authors.initials: AV
authors.lastname: Yurkovetskiy
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fram
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Lowinger
authors.forename: William C
authors.initials: WC
authors.lastname: Zamboni
mesh_terms: D000080:Acetals; D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D002853:Chromatography, Liquid; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D011108:Polymers / Q000493:pharmacokinetics* / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution; D059004:Topoisomerase I Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000080:Acetals; D011108:Polymers; D059004:Topoisomerase I Inhibitors; C546777:XMT 1001; D000077146:Irinotecan; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin