�Researchers at the Moores Cancer Center at the University of California, San Diego (UC SD) in La Jolla have establish evidence explaining why a common chemotherapy drug, cisplatin, may not always act for every cancer patient. They bear shown that when a variant version of a key protein that ordinarily causes cell death is active, patients may be resistant to the cancer-killing drug.
The scientists say that such findings, reported on-line this workweek in the journal Proceedings of the National Academy of Sciences, are authoritative to savvy how personalized therapies may be developed for patients.
In a series of experiments, Jean Wang, Ph.D., distinguished professor of medicine and Associate Director of Basic Research at the Moores UCSD Cancer Center, Richard Kolodner, Ph.D., professor of medicine at UC San Diego and Executive Director, Laboratory Science and Technology at the Ludwig Institute for Cancer Research and their co-workers found evidence that when a specific variant form of a so-called "mismatch repair" protein, PMS2, is active, cisplatin doesn't kill cancer cells the way it usually does. The cancer is, in effect, resistant to the drug.
As a quicken protein, PMS2 is crucial to fix mistakes in DNA that may occur during replication. It besides has a darker face, playing a role in instructing cells to kill themselves.
For example, Wang, Kolodner and their colleagues had previously shown that PMS2 is required for cisplatin to kill cancer cells, activating some other protein, p73, which in turn begins a cascade of steps leading to cell suicide. Since most cancer cell-killing therapies such as chemotherapy and radiation take advantage of this process, the team wanted to better understand how cancer cells might bilk such self-annihilation instructions, rendition the therapy ineffective.
Defects in such mismatch repair genes and proteins can gain cancer endangerment, particularly for hereditary colon cancer. The researchers knew that the PMS2 cistron had at least 12 different forms in man. In studies on black eye cells wanting PMS2, they tested several different variations of the human PMS2 protein, for the most part display that PMS2 indeed hypersensitized cells to cisplatin, causing cell felo-de-se. They last found that one variant, PMS2 (R20Q), failed to activate p73 and bring about cubicle death in response to cisplatin. The drug's toxic effects were compromised in cells with the PMS2 (R20Q).
Wang sees many possibilities for future research. "We don't know how many people have this PMS2 variant," she explained, noting that cisplatin is the first-line therapy for testicular and ovarian cancers. "We would like to take these findings to human tumor samples. If we could discover out which individuals carry this version, it power change our decisions about treating them with cisplatin."
If researchers could track how fast ovarian cancer patients' tumors develop resistance to cisplatin, she said, correlativity studies might be performed to regain risk factors, such as gene variants.
Ideally, scientists will ultimately intention new drugs that lavatory push cancer cells into cell self-destruction, rather than repairing themselves, she noted.
Other authors admit Irina Hunton and Atsuko Yoshioka-Yamashita, Ph.D,. UC San Diego, Winfried Edelmann, Ph.D., and Elena Avdievich, Ph.D., Albert Einstein College of Medicine, Ivana Marinovic-Terzic, M.D., University of Split, Croatia, and Hideki Shimodaira, Ph.D., Tohoko University, Japan.
The work received financing support from the National Institute for Environmental Health Sciences, the National Cancer Institute and the Japan Society for the Promotion of Science Research Fellowships for Young Scientists.
Source: Steve Benowitz
University of California - San Diego
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Tuesday, 2 September 2008
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