Antiangiogenesis Strategies Proving Valuable Against Breast and Prostate Cancer

As a tumor grows, so does its need for nutrients, with a new vascularsupply necessary for a tumor to grow to a diameter beyond 0.5 mm. Thus,many tumors secrete factors that promote the formation of blood vesselsin host tissue. Inhibition of angiogenesis and the resultant deprivationof needed nutrients may help prevent tumor growth. Data reported at the88th Annual Meeting of the American Association for Cancer Research (AACR)indicate that agents which target angiogenesis may indeed be useful intreating breast and prostate cancer.

Michael O. Meyers, MD, and Eugene W. Henry, MD, at Louisiana State UniversityMedical Center in New Orleans studied tamoxifen to determine whether itinhibits angiogenesis. Tamoxifen has been demonstrated to be most efficaciousin breast cancer patients whose tumors are estrogen-receptor-positive.However, tamoxifen also has shown benefit in a minority of patients whoare estrogen-receptor-negative, leading investigators to hypothesize thattamoxifen might have an effect other than its known hormonal effect.

The study investigators developed a model of angiogenesis using humanplacental veins and exposed the model to tamoxifen at various concentrations,evaluating the incidence of angiogenesis 6, 9, and 12 days later. Theyfound that tamoxifen at high doses significantly inhibited initiation ofangiogenesis.

According to Dr. Meyers, "Our study findings suggest that tamoxifenat high doses is an inhibitor of angiogenesis. By administering tamoxifenat higher doses than those currently used in the treatment of breast cancer,we may be able to produce better response rates in patients. We plan toconduct animal studies to investigate tamoxifen's antiangiogenesis effectfurther, and hope eventually to study this agent in clinical trials."

John T. Isaacs, PhD, and his colleagues at Johns Hopkins UniversitySchool of Medicine evaluated antiangiogenic approaches to the preventionand treatment of prostate cancer. Prostate cancers are initially dependenton androgens for their growth and are responsive to androgen ablation therapy.However, prostate cancers usually progress to an androgen-independent state.Once this occurs, the disease is rarely curable because there are few effectivechemotherapeutic agents for prostate cancer that target androgen-independentcells. As a result, alternative approaches are needed to treat androgen-independentprostate cancer.

The researchers studied linomide, an agent that has been shown in anumber of studies to have antitumor effects in prostate cancer throughits ability to inhibit tumor angiogenesis. The antiangiogenic ability oflinomide results in a reduction in the number of tumor blood vessels anda subsequent reduction in tumor blood flow, and it can inhibit the metastaticability of prostate cancer. Other studies have demonstrated that linomide,via its antiangiogenesis ability, has antitumor effects against both androgen-dependentand androgen-independent prostate cancers.

Carcinogen Plus Testosterone vs Linomide

In a study conducted in Dr. Isaacs' lab by Ingrid B. J. K. Joseph, DVM,PhD, a carcinogen and testosterone were used to induce seminal vesicle/prostatetumors and promote their growth in male rats. The rats were then treatedwith linomide for 12 months. Although about 90% of rats typically developtumors when exposed to the carcinogen and testosterone, the investigatorsfound that only 50% of those treated with linomide developed seminal vesicle/prostatetumors. Moreover, linomide appeared to reduce the number of primary tumorsas well as the number of metastatic tumors in the rats. When linomide wascombined with androgen ablation therapy, it inhibited the growth of prostatetumors and suppressed this growth for as long as the rats continued toreceive the combined therapy. In another study of female rats challengedwith a carcinogen, linomide inhibited mammary carcinogenesis in more thanhalf of the rats after five months.

According to Dr. Isaacs, "Because of their different but complementarymechanisms of action, linomide and androgen ablation therapy administeredsimultaneously was able to curtail the growth of prostate tumors betterthan either treatment administered alone. These results are so promisingthat this combination therapy warrants testing in humans to determine itseffect on prostate cancer."