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Preclinical Results of the Camptothecin-Polymer Conjugate IT-101 in Multiple Human Lymphoma Xenografts.

Camptothecin (CPT), a natural alkaloid isolated from Camptotheca acuminata , has potent broad spectrum antitumor activity by inhibiting type I DNA topoisomerase. 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 refractory/relapsed lymphoma, but with only modest activity. For intravenous administration, we have developed IT-101, a ca. 40 nm diameter nanoparticle that is an assembly of cyclodextrin-based polymer conjugates of 20-( S )-CPT. The purpose of this study is to compare the preclinical efficacy of IT-101 with CPT-11 both in vitro and in vivo . Fluorescence microscopy studies demonstrated that incubation of a human lymphoma cell line with IT-101 resulted in the uptake and intracellular accumulation of CPT. Based on the demonstration of in vitro cytotoxity of IT-101 against multiple human lymphoma cell lines, we initiated experiments in xenograft models of lymphoma. In subcutaneous human xenograft models, a single cycle of three weekly doses of intravenous IT-101 at 10 mg/kg (CPT equivalents) showed significantly potent antitumor activity against Daudi, Karpas 299, and L540 cell lines compared to three weekly doses of intraperitoneal CPT-11 at its maximum tolerated dose in mouse of 100 mg/kg ( P P = 0.0072, and P P P = 0.0049, respectively). The promising present results in a variety of lymphomas provide the basis for a phase I/II clinical trial in patients with refractory/relapsed lymphoma.