Preclinical Efficacy of the Camptothecin-Polymer Conjugate IT-101 in Multiple Cancer Models
- 1 March 2006
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 12 (5), 1606-1614
- https://doi.org/10.1158/1078-0432.ccr-05-1566
Abstract
Preclinical efficacy of i.v. IT-101, a nanoparticulate conjugate of 20(S)-camptothecin and a cyclodextrin-based polymer, was investigated in several mouse xenografts. The effects of different multiple dosing schedules on tumor growth of LS174T colon carcinoma xenografts are elucidated. All multiple dosing schedules administered over 15 to 19 days resulted in enhanced efficacy compared with untreated or single-dose groups. Further improvements in antitumor efficacy were not observed when the dosing frequency was increased from three weekly doses to five doses at 4-day intervals or 5 days of daily dosing followed by 2 days without dosing repeated in three cycles using similar cumulative doses. This observation was attributed to the extended release characteristics of camptothecin from the polymer. Antitumor efficacy was further evaluated in mice bearing six different s.c. xenografts (LS174T and HT29 colorectal cancer, H1299 non–small-cell lung cancer, H69 small-cell lung cancer, Panc-1 pancreatic cancer, and MDA-MB-231 breast cancer) and one disseminated xenograft (TC71-luc Ewing's sarcoma). In all cases, a single treatment cycle of three weekly doses of IT-101 resulted in a significant antitumor effect. Complete tumor regression was observed in all animals bearing H1299 tumors and in the majority of animals with disseminated Ewing's sarcoma tumors. Importantly, IT-101 is effective in a number of tumors that are resistant to treatment with irinotecan (MDA-MB-231, Panc-1, and HT29), consistent with the hypothesis that polymeric drug conjugates may be able to overcome certain kinds of multidrug resistance. Taken together, these results indicate that IT-101 has good tolerability and antitumor activity against a wide range of tumors.Keywords
This publication has 25 references indexed in Scilit:
- Sequence-Specific Knockdown of EWS-FLI1 by Targeted, Nonviral Delivery of Small Interfering RNA Inhibits Tumor Growth in a Murine Model of Metastatic Ewing's SarcomaCancer Research, 2005
- P-493 A phase II study of weekly innotecan plus capecitabine for chemo-naive patients with advanced non-small cel lung cancerLung Cancer, 2005
- A phase I study of irinotecan administered on a weekly schedule in pediatric patientsPediatric Blood & Cancer, 2005
- Antitumor Activity of β-Cyclodextrin Polymer−Camptothecin ConjugatesMolecular Pharmaceutics, 2004
- Camptothecins in clinical developmentExpert Opinion on Investigational Drugs, 2004
- Synthesis of Linear, β-Cyclodextrin-Based Polymers and Their Camptothecin ConjugatesBioconjugate Chemistry, 2003
- The expression of multidrug resistance-associated protein (MRP) in pancreatic adenocarcinoma cell linesCancer Letters, 1996
- Differential Interactions of Camptothecin Lactone and Carboxylate Forms with Human Blood ComponentsBiochemistry, 1994
- On the mechanism of topoisomerase I inhibition by camptothecin: evidence for binding to an enzyme-DNA complexBiochemistry, 1989
- Plant Antitumor Agents. I. The Isolation and Structure of Camptothecin, a Novel Alkaloidal Leukemia and Tumor Inhibitor from Camptotheca acuminata1,2Journal of the American Chemical Society, 1966