Evaluation of combretastatin A-4 prodrug in a non-Hodgkin's lymphoma xenograft model: preclinical efficacy

Combretastatin A-4 prodrug (CA4P) is a new antitubulin agent currently in p hase I/II clinical trials against solid tumors. We have previously reported on the in vitro activity of CA4P against a panel of malignant human B-lymp hoid cell lines. In this study, we investigated the antitumor and the antia ngiogenic activity of CA4P in our diffuse large cell lymphoma WSU-DLCL2-SCI D mouse model. WSU-DLCL2 cells (10(7)) were injected s.c. into 5-week-old f emale ICR-SCID mice. Tumor-bearing mice were treated at the CA4P maximum to lerated dose (MTD) of 800 mg/kg in different dose/schedules. CA4P showed si gnificant antitumor activity against this lymphoma model. Best results were seen when MTD was given in two and four divided doses (400 and 200 mg/kg, respectively). CA4P given in four divided doses (4 x 200 mg/kg) showed a lo g(10) kill of 1.01, T/C of 11.7% and T-C of 12 days. Immunohistochemical st aining using anti-CD31 antibody after 6, 24, 48 and 120 h treatment reveale d a significant decrease in the number of tumor blood vessels after 24 h (a bout 80%), Only the periphery of treated tumors revealed the presence of bl ood vessels. Morphological examination of the tumors after tetrachrome stai ning showed a necrotic center in tumors of CA4P-treated animals. New blood vessel formation was noted to emerge in tumor tissues as early as 48 h foll owing a single dose of CA4P. The G(2)/M arrest observed in vitro was not de tected in vivo indicating predominance of the antiangiogenic effects with r egard to antitumor efficacy in vivo. We conclude that CA4P has antiangiogen ic activity in this lymphoma model and the use of this agent should be expl ored clinically in the treatment of non-Hodgkin's lymphoma, [(C) 2001 Lippi ncott Williams & Wilkins.].