ANTIANGIOGENIC TREATMENT WITH LINOMIDE AS CHEMOPREVENTION FOR PROSTATE, SEMINAL-VESICLE, AND BREAST CARCINOGENESIS IN RODENTS

There are two distinct phases during prostatic carcinogenesis with reg ard to tumor blood vessel development. During the first or prevascular phase, which may persist for years, cells that have undergone some bu t not all of the transformation steps undergo a limited amount of net growth, producing premalignant prostatic intraepithelial neoplastic (P IN) lesions. Most of these PIN lesions do not continue net growth and do not progress to produce histologically detectable cancer. Even the PIN lesions that do progress to cancer remain of limited virulence unl ess they undergo conversion to the second or angiogenic phase. Once th is angiogenic phase is reached, new blood vessel development is greatl y enhanced within the cancer. It is this enhanced tumor angiogenesis w hich allows these cancers both to grow continuously and to metastasize . Thus, inhibition of angiogenesis should be an effective chemoprevent ive approach for prostatic carcinogenesis. Linomide is a low molecular weight, water-soluble agent with excellent p.o. absorption and bioava ilability. We have previously demonstrated that daily p.o. treatment w ith Linomide has antiangiogenic abilities against a series of rat and human prostatic cancer xenografts growing in vivo. In the present stud ies, me have demonstrated using Matrigel in in vivo angiogenesis assay s that daily p.o. Linomide at 25 mg/kg/day inhibits angiogenesis induc ed by tumor necrosis factor or, acidic fibroblast growth factor, basic fibroblast growth factor, and vascular endothelial growth factor. Usi ng an N-methylnitrosourea initiation-androgen promotion model, Linomid e was given p.o. at a daily dose as high as 25 mg/kg/day for at least 1 year without major toxicity while inhibiting the development of semi nal vesicle/prostate cancers in male rats by >50%. Dose-response analy sis demonstrated that a Linomide blood level of 50-100 mu M is optimal for such chemoprevention. In addition, Linomide treatment at a dose o f 25 mg/kg/day was able to inhibit by approximate to 60% the incidence of N-methylnitrosourea and similar to 50% of 7,12-dimethyl-benz(a)ant hracine-induced mammary carcinogenesis in female rats.