Prevention of prostate-related cancers in Lobund-Wistar rats

BACKGROUND. Since prostate cancer (PC) development involves a combination o f genetic predisposition and promotional mechanisms, especially the metabol ic conversion of testosterone to 5 alpha. dihydrotestosterone (DHT) by 5 al pha reductase, how do mechanisms in man relate to prostate-seminal vesicle (P-SV) tumor development in Lobund-Wistar (L-W) rats? The disease in man an d in L-W rats shares developmental mechanisms and characteristics to the ex tent that prevention of P-SV tumors in L-W rats could be predictive of simi lar results in man. The epidemiology of PC in man and P-SV tumors in L-W ra ts indicates that both are hormone-related diseases based on genetic predis position, high production of androgens (which are activated to DHT by 5 alp ha reductase), and early development of androgen-dependent and metastasizin g late androgen-independent stages of adenocarcinomas, all after long laten cy periods. METHODS. L-W rats at risk of developing spontaneous or induced P-SV tumors were subjected to putative antitumor agents or procedures. These included d ietary restriction, testosterone ablation, soybean-derived isoflavones, ant iangiogenic linomide, tamoxifen, and a vitamin D analogue. RESULTS. L-W rats subjected to 1) early onset of dietary restriction manife sted suppression of spontaneous and induced development of P-SV tumors; 2) testosterone-ablation by nonesterified DHT (NE-DHT) suppressed early onset of induced P-SV tumors and to a lesser extent late onset of spontaneous tum ors; 3) diets containing soy protein isolate thigh isoflavones) manifested marginal suppressive effects against induced P-SV tumors, but in 12-month-o ld rats, the development of spontaneous tumors was reduced in incidence; 4) early administrations of antiangiogenic linomide suppressed development of induced P-SV tumors and of transplanted prostate adenocarcinoma III (PA-m) tumors, but linomide had Little antitumor effect against large advanced st age tumors; and 5) tamoxifen and vitamin D analogue suppressed development of P-SV tumors. Results in conditions 1-3 were negative when tested against PA-III tumors. CONCLUSIONS. Developing stages of P-SV tumors were prevented in L-W rats wi th autochthonous spontaneous and induced tumors, but most of the agents tes ted were of no therapeutic benefit against advanced-stage and transplanted PA-m tumors. However, early administrations of antiangiogenic linomide supp ressed early growth of induced and transplanted PA-m tumors. (C) 1999 Wiley -Liss, Inc.