As a tumor grows, so does its need for nutrients, with a new vascular
supply necessary for a tumor to grow to a diameter beyond 0.5 mm. Thus,
many tumors secrete factors that promote the formation of blood vessels
in host tissue. Inhibition of angiogenesis and the resultant deprivation
of needed nutrients may help prevent tumor growth. Data reported at the
88th Annual Meeting of the American Association for Cancer Research (AACR)
indicate that agents which target angiogenesis may indeed be useful in
treating breast and prostate cancer.
Michael O. Meyers, MD, and Eugene W. Henry, MD, at Louisiana State University
Medical Center in New Orleans studied tamoxifen to determine whether it
inhibits angiogenesis. Tamoxifen has been demonstrated to be most efficacious
in breast cancer patients whose tumors are estrogen-receptor-positive.
However, tamoxifen also has shown benefit in a minority of patients who
are estrogen-receptor-negative, leading investigators to hypothesize that
tamoxifen might have an effect other than its known hormonal effect.
The study investigators developed a model of angiogenesis using human
placental veins and exposed the model to tamoxifen at various concentrations,
evaluating the incidence of angiogenesis 6, 9, and 12 days later. They
found that tamoxifen at high doses significantly inhibited initiation of
According to Dr. Meyers, "Our study findings suggest that tamoxifen
at high doses is an inhibitor of angiogenesis. By administering tamoxifen
at 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 to
conduct animal studies to investigate tamoxifen's antiangiogenesis effect
further, and hope eventually to study this agent in clinical trials."
John T. Isaacs, PhD, and his colleagues at Johns Hopkins University
School of Medicine evaluated antiangiogenic approaches to the prevention
and treatment of prostate cancer. Prostate cancers are initially dependent
on 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 effective
chemotherapeutic agents for prostate cancer that target androgen-independent
cells. As a result, alternative approaches are needed to treat androgen-independent
The researchers studied linomide, an agent that has been shown in a
number of studies to have antitumor effects in prostate cancer through
its ability to inhibit tumor angiogenesis. The antiangiogenic ability of
linomide results in a reduction in the number of tumor blood vessels and
a subsequent reduction in tumor blood flow, and it can inhibit the metastatic
ability of prostate cancer. Other studies have demonstrated that linomide,
via its antiangiogenesis ability, has antitumor effects against both androgen-dependent
and 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/prostate
tumors and promote their growth in male rats. The rats were then treated
with linomide for 12 months. Although about 90% of rats typically develop
tumors when exposed to the carcinogen and testosterone, the investigators
found that only 50% of those treated with linomide developed seminal vesicle/prostate
tumors. Moreover, linomide appeared to reduce the number of primary tumors
as well as the number of metastatic tumors in the rats. When linomide was
combined with androgen ablation therapy, it inhibited the growth of prostate
tumors and suppressed this growth for as long as the rats continued to
receive the combined therapy. In another study of female rats challenged
with a carcinogen, linomide inhibited mammary carcinogenesis in more than
half of the rats after five months.
According to Dr. Isaacs, "Because of their different but complementary
mechanisms of action, linomide and androgen ablation therapy administered
simultaneously was able to curtail the growth of prostate tumors better
than either treatment administered alone. These results are so promising
that this combination therapy warrants testing in humans to determine its
effect on prostate cancer."