Science Current Events | Science News | Brightsurf.com
 
Email a Friend Send to a friend
Printer Friendly Print Variation of normal protein could be key to resistance to common cancer drug

Variation of normal protein could be key to resistance to common cancer drug

August 28, 2008

Researchers at the Moores Cancer Center at the University of California, San Diego (UC SD) in La Jolla have found evidence explaining why a common chemotherapy drug, cisplatin, may not always work for every cancer patient. They have shown that when a variant version of a key protein that normally causes cell death is active, patients may be resistant to the cancer-killing drug.

The scientists say that such findings, reported online this week in the journal Proceedings of the National Academy of Sciences, are important to understanding 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 normally does. The cancer is, in effect, resistant to the drug.

As a repair protein, PMS2 is crucial to fixing mistakes in DNA that may occur during replication. It also has a darker side, playing a role in instructing cells to kill themselves.

For example, Wang, Kolodner and their colleagues had previously shown that PMS2 is needed for cisplatin to kill cancer cells, activating another 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 evade such suicide instructions, rendering the therapy ineffective.

Defects in such mismatch repair genes and proteins can increase cancer risk, particularly for hereditary colon cancer. The researchers knew that the PMS2 gene had at least 12 different forms in humans. In studies on mouse cells lacking PMS2, they tested several different variations of the human PMS2 protein, for the most part showing that PMS2 indeed sensitized cells to cisplatin, causing cell suicide. They finally found that one variant, PMS2 (R20Q), failed to activate p73 and bring about cell 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 find out which individuals carry this variant, it might change our decisions about treating them with cisplatin."

If researchers could track how fast ovarian cancer patients' tumors develop resistance to cisplatin, she said, correlation studies might be performed to find risk factors, such as gene variants.

Ideally, scientists will ultimately design new drugs that can push cancer cells into cell suicide, rather than repairing themselves, she noted.

University of California - San Diego



Related Cisplatin Current Events and Cisplatin News Articles Cisplatin Current Events and Cisplatin News RSS Cisplatin Current Events and Cisplatin News RSS
New platinum-phosphate compounds kill ovarian cancer cells
A new class of compounds called phosphaplatins can effectively kill ovarian, testicular, head and neck cancer cells with potentially less toxicity than conventional drugs, according to a new study published this week in the journal Proceedings of the National Academy of Sciences.

New clinical trial for patients with asbestos-associated lung cancer
The Mesothelioma Center within the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian Hospital and Columbia University Medical Center is now recruiting patients for a clinical research study of a new targeted radiation and chemotherapy protocol for pleural mesothelioma, a cancer of the lung's lining that is almost always caused by previous exposure to asbestos.

MIT researchers see alternative to common colorectal cancer drug
A compound that accumulates in cells more readily than a commonly used colorectal cancer drug may be just as useful in treating colorectal tumors, but with fewer side effects, MIT researchers have found.

Synergistic growth inhibitory effect of herbal extracts against HCC and lung cancer cells
Several herbs with diversified pharmacological properties are known to be rich sources of chemical constituents that may have potential for the treatment of several human cancers. Data from the Department of Preclinical Science, Faculty of Medicine, Thammasat University, demonstrates that the growth inhibitory activity of doxorubicin or cisplatin, as single agents, may be modified in combination with emblic myrobalan or belleric myrobalan extracts and may be synergistically enhanced in some cases.

Analysis shows combining sorafenib with carboplatin/paclitaxel adds no benefit in lung cancer
A clinical trial evaluating the benefit of adding the drug sorafenib to the combination of carboplatin/paclitaxel chemotherapy for lung cancer patients has been stopped based on results from an interim analysis, after an independent data monitoring committee concluded that the study would not meet its primary endpoint of improved overall survival.

Study finds cisplatin less effective than standard treatment for patients with anal cancer
When administered before chemoradiation, the common anti-cancer drug cisplatin neither improved disease-free survival nor reduced the number of colostomies needed when compared to the standard treatment for patients with anal canal cancer, according to a study published in the April 23 issue of the Journal of the American Medical Association.

Study reveals why certain ovarian cancers develop resistance to platinum-based chemotherapy
A team of researchers led by Fred Hutchinson Cancer Research Center has identified a new mechanism that explains why some recurrent ovarian tumors become resistant to treatment with commonly used platinum-based chemotherapy drugs such as cisplatin and carboplatin. They describe their research online Feb. 10 in the journal Nature.

Light powered platinum more targeted & 80 times more powerful than similar cancer treatments
Researchers from the Universities of Warwick, Edinburgh, Dundee and the Czech Republic's Institute of Biophysics have discovered a new light-activated platinum-based compound that is up to 80 times more powerful than other platinum-based anti-cancer drugs and which can use "light activation" to kill cancer cells in much more targeted way than similar treatments.

New treatment option studied for bladder cancer
A chemotherapy regimen for patients with advanced bladder cancer who aren't eligible for standard treatment is under study at the Medical College of Georgia.

Mayo Clinic reports possible new therapy for patients with platinum-resistant ovarian cancer
Mayo Clinic today reported promising interim results from a Phase II trial of a new combination therapy for patients with recurrent ovarian cancer that is resistant to platinum therapy. Thirty-three percent of study participants achieved either complete or partial tumor regression from the therapy, which combines flavopiridol and cisplatin.
More Cisplatin Current Events and Cisplatin News Articles


Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug

30 years after its discovery as an antitumor agent, cisplatin represents today one of the most successful drugs in chemotherapy. This book is intended to reminisce this event, to take inventory, and to point out new lines of development in this field. Divided in 6 sections and 22 chapters, the book provides an up-to-date account on topics such as the chemistry and biochemistry of...

The Mechanism of Cisplatin Resistance and Its Circumvention



Cisplatin induces DNA double-strand break formation in Escherichia coli dam mutants [An article from: DNA Repair]
by A. Nowosielska, M.G. Marinus

This digital document is a journal article from DNA Repair, published by Elsevier in . The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser.Description: Escherichia coli dam cells are more susceptible to the cytotoxic action of cisplatin than wildtype. Dam mutS or dam mutL bacteria, however, are...



Spontaneous and cisplatin-induced recombination in Escherichia coli [An article from: DNA Repair]
by A. Nowosielska, M.A. Calmann, Z. Zdraveski, Essigm

This digital document is a journal article from DNA Repair, published by Elsevier in 2004. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser.Description: To measure cisplatin (cis-diaminodichloroplatinum(II))-induced recombination, we have used a qualitative intrachromosomal assay utilizing...

MVAC Regimen, Cystectomy Add Life in Bladder Ca.(methotrexate, vinblastine, doxorubicin, and cisplatin for the treatment of metastatic bladder cancer): An article from: Internal Medicine News
by Timothy F. Kirn

This digital document is an article from Internal Medicine News, published by International Medical News Group on July 15, 2001. The length of the article is 328 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser.Citation...



Immortalized mouse cell lines that lack a functional Rev3 gene are hypersensitive to UV irradiation and cisplatin treatment [An article from: DNA Repair]
by L. Zander, M. Bemark

This digital document is a journal article from DNA Repair, published by Elsevier in 2004. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser.Description: The catalytic subunit of polymerase @z is encoded from the Rev3 gene. The enzyme is conserved through eukaryotic evolution and its main...

Cisplatin: An entry from Thomson Gale's Gale Encyclopedia of Cancer, 2nd ed.
by Nancy, RPh., BCOP Beaulieu, Rebecca, PhD Frey

Students, researchers, and patients can find reliable, up-to-date and clearly written information in “The Gale Encyclopedia of Cancer,” a comprehensive survey of 120 cancers, cancer drugs, traditional and alternative treatments and diagnostic...

Buyer's Guide to Boots & Wraps / Khemosabi: The All-American Arabian / Pain as Nature's Alarm / Reduce Performance Risks / Mind Power for Better Riding / Japanese Flu Vaccine / Cisplatin Update / Dampening Dust in Forage (Equus, Issue 237, July 1997)

Effect of Cassia auriculata Linn. Root extract on cisplatin and gentamicin-induced renal injury.: An article from: Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
by S. Annie, P.L. Rajagopal, S. Malini

This digital document is an article from Phytomedicine: International Journal of Phytotherapy & Phytopharmacology, published by Thomson Gale on August 1, 2005. The length of the article is 3558 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view...

Gale Encyclopedia of Cancer: Cisplatin
by RPh., BCOP Nancy J. Beaulieu

The article is excerpted from Gale Encyclopedia of Cancer The resource students and researchers will turn to for reliable, up-to-date and clearly written information, the Gale Encyclopedia of Cancer is a comprehensive survey of 120 cancers, cancer drugs, traditional and alternative treatments and diagnostic procedures. The Encyclopedia includes entries covering cancers, cancer drugs,...

© 2008 BrightSurf.com