Preclinical results of camptothecin-polymer conjugate (IT-101) in multiple human lymphoma xenograft models

Tontanai Numbenjapon, Jianyi Wang, David Colcher, Thomas Schluep, Mark E. Davis, Julienne Duringer, Leo Kretzner, Yun Yen, Stephen J. Forman, Andrew Raubitschek

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49 引文 斯高帕斯(Scopus)

摘要

Purpose: Camptothecin (CPT) has potent broad-spectrum antitumor activity by inhibiting type I DNA topoisomerase (DNA topo I). It has not been used clinically because it is water-insoluble and highly toxic. As a result, irinotecan (CPT-11), a water-soluble analogue of CPT, has been developed and used as salvage chemotherapy in patients with relapsed/refractory lymphoma, but with only modest activity. Recently, we have developed a cyclodextrin-based polymer conjugate of 20-(S)-CPT (IT-101). In this study, we evaluated the preclinical antilymphoma efficacy of IT-101 as compared with CPT-11. Experimental Design: We determined an in vitro cytotoxicity of IT-101, CPT-11, and their metabolites against multiple human lymphoma cell lines. In human lymphoma xenografts, the pharmacokinetics, inhibitions of tumor DNA topo I catalytic activity, and antilymphoma activities of these compounds were evaluated. Results: IT-101 and CPT had very high in vitro cytotoxicity against all lymphoma cell lines tested. As compared with CPT-11 and SN-38, IT-101 and CPT had longer release kinetics and significantly inhibit higher tumor DNA topo I catalytic activities. Furthermore, IT-101 showed significantly prolonged the survival of animals bearing s.c. and disseminated human xenografts when compared with CPT-11 at its maximum tolerated dose in mice. Conclusions: The promising present results provide the basis for a phase I clinical trial in patients with relapsed/refractory lymphoma.

原文英語
頁(從 - 到)4365-4373
頁數9
期刊Clinical Cancer Research
15
發行號13
DOIs
出版狀態已發佈 - 7月 1 2009
對外發佈

ASJC Scopus subject areas

  • 腫瘤科
  • 癌症研究

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