There are two distinct phases during prostatic
carcinogenesis with regard to
tumor blood vessel development. During the first or prevascular phase, which may persist for years, cells that have undergone some but not all of the transformation steps undergo a limited amount of net growth, producing premalignant prostatic intraepithelial neoplastic (PIN) 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 unless they undergo conversion to the second or angiogenic phase. Once this angiogenic phase is reached, new blood vessel development is greatly enhanced within the
cancer. It is this enhanced
tumor angiogenesis which allows these
cancers both to grow continuously and to metastasize. Thus, inhibition of angiogenesis should be an effective chemopreventive approach for prostatic
carcinogenesis.
Linomide is a low molecular weight, water-soluble agent with excellent p.o. absorption and bioavailability. We have previously demonstrated that daily p.o. treatment with
Linomide has antiangiogenic abilities against a series of rat and human
prostatic cancer xenografts growing in vivo. In the present studies, we have demonstrated using
Matrigel in in vivo angiogenesis assays that daily p.o.
Linomide at 25 mg/kg/day inhibits angiogenesis induced by
tumor necrosis factor alpha,
acidic fibroblast growth factor,
basic fibroblast growth factor, and
vascular endothelial growth factor. Using an N-
methylnitrosourea initiation-
androgen promotion model,
Linomide 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 seminal vesicle/
prostate cancers in male rats by >50%. Dose-response analysis demonstrated that a
Linomide blood level of 50-100 microM is optimal for such
chemoprevention. In addition,
Linomide treatment at a dose of 25 mg/kg/day was able to inhibit by approximately 60% the incidence of N-
methylnitrosourea and approximately 50% of 7,12-dimethyl-benz(a)anthracine-induced mammary
carcinogenesis in female rats.