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Antiangiogenic Treatment with Linomide as Chemoprevention for Prostate, Seminal Vesicle, and Breast Carcinogenesis in Rodents¹

Johns Hopkins Oncology Center [I. B. J. K. J., J. T. I.] and Department of Urology [J. T. I.], The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and Vanderbilt University Hospital [J. V.], Nashville, Tennessee 37232-2358

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 , 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 µM is optimal for such chemoprevention. In addition, Linomide treatment at a dose of 25 mg/kg/day was able to inhibit by 60% the incidence of N-methylnitrosourea and 50% of 7,12-dimethyl-benz(a)anthracine-induced mammary carcinogenesis in female rats.

¹ Supported by NIH Grant CA62482.

² To whom requests for reprints should be addressed, at Johns Hopkins Oncology Center, 422 North Bond Street, Baltimore, MD 21231-1001.

Received 4/29/96. Accepted 5/29/96.

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