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

Abstract

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 (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: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 9 Pg. 2591-602 (May 01 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22392910 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• Acetals
• Polymers
• Topoisomerase I Inhibitors
• XMT 1001
• Irinotecan
• DNA Topoisomerases, Type I
• Camptothecin

Topics

• Acetals
• Animals
• Camptothecin (analogs & derivatives, pharmacokinetics, pharmacology)
• Chromatography, Liquid
• Colonic Neoplasms (drug therapy)
• DNA Topoisomerases, Type I (chemistry, metabolism)
• Female
• Humans
• Irinotecan
• Mice
• Mice, Nude
• Polymers (pharmacokinetics, pharmacology)
• Tandem Mass Spectrometry
• Tissue Distribution
• Topoisomerase I Inhibitors (pharmacokinetics, pharmacology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays