Prevention of prostate-related cancers in Lobund-Wistar rats.
BACKGROUND
Since prostate cancer (PC) development involves a combination of genetic predisposition and promotional mechanisms, especially the metabolic conversion of testosterone to 5alpha dihydrotestosterone (DHT) by 5alpha 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 and in L-W rats shares developmental mechanisms and characteristics to the extent that prevention of P-SV tumors in L-W rats could be predictive of similar results in man. The epidemiology of PC in man and P-SV tumors in L-W rats indicates that both are hormone-related diseases based on genetic predisposition, high production of androgens (which are activated to DHT by 5alpha reductase), and early development of androgen-dependent and metastasizing late androgen-independent stages of adenocarcinomas, all after long latency 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 dietary restriction, testosterone ablation, soybean-derived isoflavones, antiangiogenic linomide, tamoxifen, and a vitamin D analogue.


RESULTS
L-W rats subjected to 1) early onset of dietary restriction manifested 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 tumors; 3) diets containing soy protein isolate (high isoflavones) manifested marginal suppressive effects against induced P-SV tumors, but in 12-month-old 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-III) tumors, but linomide had little antitumor effect against large advanced stage 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 with autochthonous spontaneous and induced tumors, but most of the agents tested were of no therapeutic benefit against advanced-stage and transplanted PA-III tumors. However, early administrations of antiangiogenic linomide suppressed early growth of induced and transplanted PA-III tumors.
Pollard
M
M
Lobund Laboratory, University of Notre Dame, Indiana 46556, USA.
D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D004198:Disease Susceptibility; D004968:Estrogens, Non-Steroidal / Q000627:therapeutic use; D006912:Hydroxyquinolines / Q000627:therapeutic use; D007529:Isoflavones / Q000627:therapeutic use; D008297:Male; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D048789:Phytoestrogens; D028321:Plant Preparations; D011471:Prostatic Neoplasms / Q000178:diet therapy / Q000188:drug therapy / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D013025:Glycine max; D013629:Tamoxifen / Q000627:therapeutic use; D013739:Testosterone / Q000037:antagonists & inhibitors; D014807:Vitamin D / Q000031:analogs & derivatives / Q000627:therapeutic use
D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D004968:Estrogens, Non-Steroidal; D006912:Hydroxyquinolines; D007529:Isoflavones; D048789:Phytoestrogens; D028321:Plant Preparations; D013629:Tamoxifen; D014807:Vitamin D; C045282:roquinimex; D013739:Testosterone