Preclinical Results of Camptothecin-Polymer Conjugate (IT-101) in Multiple Human Lymphoma Xenograft Models
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...
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Veröffentlicht in: | Clinical cancer research 2009-07, Vol.15 (13), p.4365-4373 |
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Zusammenfassung: | 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. |
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ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.CCR-08-2619 |