Exsulind (sulindac sulfone) suppresses growth of human prostate cancer in a nude mouse xenograft model by increasing apoptosis

Objectives. Recent studies have shown that Exisulind, a sulfone metabolite of the nonsteroidal antiinflammatory drug (NSAID) sulindac, has inhibitory activity in vitro with cultured human prostate cancer cells. To determine w hether this effect might be pharmacologically relevant in vivo, we tested w hether Exisulind therapy could suppress the growth of human prostate cancer cells in a nude mouse xenograft model. Methods. Thirty athymic nude mice were injected subcutaneously in the flank with 1 x 10(7) LNCaP human prostate tumor cells. All mice received a contr ol diet for 21 days. One group of mice was continued on this control diet f or an additional 4 weeks, a second group was switched to a diet supplemente d with 0.05% Exisulind (40% of maximal tolerated dose [MTD]), and a third g roup was switched to a diet supplemented with 0.1% Exisulind (80% MTD) for the additional 4 weeks. Tumor growth was measured through the 4-week test p eriod, and subsequently tissue sections from the various groups were tested for apoptotic and dividing cells by quantified use of the TUNEL assay and a bromodeoxyuridine (BrdU) incorporation immunoassay. Results. Tumors grew by 158%, 24%, and 18% for the control and 0.05% and 0. 1% Exisulind groups, respectively (P = 0.02) during the 4-week test period. Immunohistochemical studies on excised tumors showed an increased number o f apoptotic bodies in the treated groups versus the control group (P < 0.00 01) but no change in the number of BrdU positive cells. Conclusions. This is the first study to show a direct in vivo effect of an NSAID-derived drug, lacking cyclooxygenase inhibitory activity, in a xenogr aft model of prostate cancer. Clinical studies to evaluate the effects of E xisulind against prostate cancer in humans are warranted. (C) 1999, Elsevie r Science Inc. All rights reserved.