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The In ovo CAM-assay as a Xenograft Model for Sarcoma
Published on: July 17, 2013
Preclinical results of camptothecin-polymer conjugate (IT-101) in multiple human lymphoma xenograft models
Tontanai Numbenjapon1, Jianyi Wang, David Colcher
1Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute at City of Hope, City of Hope Comprehensive Cancer Center, Duarte, California, USA.
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.
