Numbenjapon, Tontanai and Wang, Jianyi and Colcher, David and Schluep, Thomas and Davis, Mark E. and Duringer, Julienne and Kretzner, Leo and Yen, Yun and Forman, Stephen J. and Raubitschek, Andrew (2009) Preclinical Results of Camptothecin-Polymer Conjugate (IT-101) in Multiple Human Lymphoma Xenograft Models. Clinical Cancer Research, 15 (13). pp. 4365-4373. ISSN 1078-0432 http://resolver.caltech.edu/CaltechAUTHORS:20090903-095514247
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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.
|Additional Information:||© 2009 American Association for Cancer Research. Received 11/27/08; revised 2/18/09; accepted 2/21/09. Published Online First June 23, 2009; doi: 10.1158/1078-0432.CCR-08-2619 We thank Christopher Ruel for help with statistical analysis; City of Hope's Animal Resource Center under the direction of Dr. Richard Ermel, Patty Wong, and, Aaron Shoop for help with animal experiments; Dr. Peiguo Chu, Dr. Karen Chang, and Sofia Loera for help with histopathologic staining and reviews; and Linling Chen for help with Topo I catalytic activity study. Grant support: City of Hope Lymphoma SPORE Grant (P50 CA107399). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Specific Contributions: T. Numbenjapon, J. Wang, D. Colcher, T. Schluep, M.E. Davis, L. Kretzner, Y. Yen, S.J. Forman, and A. Raubitschek designed the research; T. Numbenjapon, J. Wang, J. Duringer, and L. Kretzner performed research; T. Schluep provided vital reagent; M.E. Davis developed vital reagent; T. Numbenjapon, J. Wang, D. Colcher, L. Kretzner, and S.J. Forman wrote the manuscript.|
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|Deposited By:||George Porter|
|Deposited On:||18 Sep 2009 22:51|
|Last Modified:||26 Dec 2012 11:18|
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