Cancer Therapy: Preclinical Pharmacokinetics and Antitumor Efficacy of XMT-1001, a Novel, Polymeric Topoisomerase I Inhibitor, in Mice Bearing HT-29 Human Colon Carcinoma Xenografts

نویسندگان

  • Mark D. Walsh
  • Suzan K. Hanna
  • Jeremy Sen
  • Sumit Rawal
  • Carolina B. Cabral
  • Alex V. Yurkovetskiy
  • Robert J. Fram
  • Timothy B. Lowinger
  • William C. Zamboni
چکیده

Purpose: 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. Experimental Design: 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 (n1⁄4 10) at 15, 30, and 60mg 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 60mgCPT equivalents/kg 1 via tail vein or an equimolar dose of CPT11 at 100 mg/kg i.p. 1. Mice (n1⁄4 3 per time point) were euthanized from 0.083 to 336 hours after XMT1001 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 XMT1001, 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 andCPT-SA, and active CPT, whichwas 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. Clin Cancer Res; 18(9); 2591–602. 2012 AACR.

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Pharmacokinetics and antitumor efficacy of XMT-1001, a novel, polymeric topoisomerase I inhibitor, in mice bearing HT-29 human colon carcinoma xenografts.

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تاریخ انتشار 2012