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| From OncoLog,
September 2006, Vol. 51, No. 9 |
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Drug Combination Promising for Metastatic Prostate Cancer
M. D. Anderson scientists previously showed that the use of a combination of imatinib (Gleevec) and paclitaxel (Taxol) to block platelet-derived growth factor receptors (PDGF-R) in an extremely drug-resistant mouse model of metastatic prostate cancer effectively reduced the size of tumors and cut the incidence of metastasis. In a follow-up study, published in the June 7 issue of the Journal of the National Cancer Institute, the researchers examined whether the combined agents worked by attacking tumor cells or tumor-related blood vessels. They found that tumor-associated endothelial cells seemed to be the target for imatinib and chemotherapy, rather than the tumor cells.
When imatinib and paclitaxel were administered in combination to mice with a multiple-drug–resistant form of prostate cancer, the incidence of bone metastases and the size of tumors were significantly reduced. Tumors were found in only 4 of 18 mice treated with the combination, median tumor weight was one-tenth of a gram, and the cancer spread to the lymph nodes in three mice. By comparison, tumors grew in all 19 control mice, the median tumor weight was 1.3 grams, and all mice had lymph node metastasis.
Isaiah J. Fidler, Ph.D., chair of the Department of Cancer Biology and director of the Cancer Metastasis Research Center at M. D. Anderson, and colleagues showed that imatinib inhibited phosphorylation of PDGF-R in tumor-associated endothelial cells, rendering these cells sensitive to apoptosis mediated by chemotherapy. The death of blood vessel cells led to the death of surrounding tumor cells. Dr. Fidler said these findings are a vibrant example of the “seed and soil” hypothesis in metastasis—that when metastatic cells enter the circulation, most die off quickly and the cells that survive do so because they find a microenvironment specifically conducive to their growth. For prostate cancer, that’s bone. “Here, we attack the endothelial cells themselves, and killing the vasculature prevents survival of the tumor cells,” he explained.
Based on these promising laboratory results, researchers at M. D. Anderson are now leading a phase II clinical trial testing imatinib and docetaxel (which is in the same family of drugs as paclitaxel) in androgen-independent prostate cancer.
Chronic Stress Promotes Ovarian Tumor Growth
Many people believe that a connection exists between high levels of stress and cancer, but there has been little scientific proof until now. In the August issue of the journal Nature Medicine, M. D. Anderson researchers have shown the first measurable link between psychological stress and the biological processes that make ovarian tumors grow and spread.
When the researchers induced chronic stress in mice with ovarian cancer, the tumors of the mice grew and spread more quickly. “This study provides a new understanding of how chronic stress and stress factors drive tumor growth,” said Anil Sood, M.D., professor of gynecologic oncology and cancer biology and director of ovarian cancer research.
“The concept of stress hormone receptors directly driving cancer growth is very new,” said Dr. Sood, the study’s senior author. “Not much had been known about how often these receptors are expressed in cancer, and more importantly, whether they had any functional significance. Our research opens a new area of investigation.”
The research began when Dr. Sood and his colleague, Susan Lutgendorf, found an association between ovarian cancer patients who reported high levels of distress in their lives and an increase in the ß2 adrenergic receptor that stimulates blood vessel growth in tumors. By contrast, patients who reported more social support in their lives had lower levels of this factor. Dr. Sood wondered if hormones associated with chronic stress might affect how cancers grow.
Dr. Sood’s research team developed a mouse model of ovarian cancer to study the link. The researchers confined the mice in a small space for zero, 2, or 6 hours during the day, which caused the mice to produce the same stress hormones humans produce under stress.
Dr. Sood and his colleagues found that, surprisingly, cancer cells make receptors for these hormones on their surface and that when these receptors are activated they set in motion a chain of events that leads to angiogenesis, allowing tumors to grow and spread more rapidly.
After 3 weeks, the researchers measured the number and size of tumors in the mice. The number of tumors was 2.5 times greater in the mice that had been in the 2-hour stress group and 3.6 times greater in the 6-hour stress group compared with the mice with no stress. In addition, tumor growth was confined in the no-stress mice but had spread to the liver or spleen in half of the stressed mice.
Researchers also found that when they blocked the stress hormone receptors in their experimental system using the beta blocker propranolol, they also stopped the negative effects of stress on tumor growth. “The medication neutralized the effect of stress on tumor growth,” said Dr. Sood.
“Beta blockers have been shown to be protective against cardiac disease,” he said. “No one has studied their effect on chronic stress as it relates to cancer in humans. There is a lot of interest now in this area of combining behavioral interventions to reduce stress, as well as looking at the use of beta blockers in cancer patients.”
For
more information on this topic or for questions about M. D. Anderson’s treatments,
programs, or services, call askMDAnderson at (877) MDA-6789.
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