|
Genes identified that protect against heart damage from chemotherapy
December 04, 2007A series of genes that protect cells from the powerful, common chemotherapeutic agent doxorubicin has been identified by researchers working to understand how the drug also can destroy the heart.
"We found a series of genes that are very important for cell survival in the face of doxorubicin," says Dr. Hernan Flores-Rozas, cancer researcher at the Medical College of Georgia Cancer Center. "At the moment you start inactivating these genes, the cells become very sensitive and don't grow any more. So now we know which genes we need to inactivate in the cell to make it very sensitive to the drug."
Doxorubicin is widely used to treat solid tumors from breast cancer to prostate and ovarian cancer. A slightly modified version, daunorubicin, is a powerful fighter of leukemia and lymphoma and often is used in children.
Unfortunately, just as cancer treatment ends, heart problems can begin for some patients who get these drugs. Heart cells, called cardiomyocytes, can commit suicide, or apoptosis, says Dr. Ling Xia, a graduate student at the Department of Cardiology at China's Wuhan University who is part of an exchange program with MCG. The result is dilative cardiomyopathy, in which the heart becomes a boggy organ that can no longer pump blood out to the body. Damage can even show up years after treatment, she says noting there is no known way to prevent or treat it, short of a heart transplant.
The long-term goal of their research is prevention and maybe enhanced cancer treatment through development of ways to turn these genes off in cancer cells and on in heart cells, says Dr. Flores-Rozas, corresponding author on the study published in the Dec. 1 issue of Cancer Research. Dr. Xia is first author.
Another possibility is turning down their protection in cancer cells, which should necessitate less drug and result in less heart damage, says Dr. Flores-Rozas, noting that it's dose related and cumulative.
They did studies in relatively simple yeast cells from Dr. Anil Cashikar's yeast knockout collection. Yeast, which have about 6,000 genes compared to humans' 30,000, are good models for study of human cells because they include the same basic cellular functions such as replication, DNA repair, signaling and even cell death, says Dr. Cashikar, MCG geneticist and a study co-author.
They found 71 genes that conveyed varying degree of protection from doxorubicin. "The cell does not have a unique mechanism to protect from doxorubicin; it's a very complex response," says Dr. Flores-Rozas. "Some genes protect better than others. But in the absence of some of these genes, the cells will die from exposure to the drug."
The genes may even protect cancer and cardiac cells differently, he says noting one way doxorubicin stops cancer cells is by preventing their classic rapid division. Cardiac cells, on the other hand, don't divide. Still there's some common ground between the cells when it comes to protection. Cardiac cells have been known to use heat shock proteins to protect themselves from toxic injuries. This enables proteins made by cells to continue to function properly. "If you have activated heat shock response, you have more activate proteins," says Dr. Flores-Rozas. "If you have proteins that don't function, the cell is eventually going to die." The MCG researchers have shown the heat shock response also is activated in a stressed cancer cell.
He notes these newly identified protective genes likely already are expressed at some level before the cells are confronted with a stress such as a chemotherapeutic agent, then step up expression in response. "If it doesn't, doxorubicin will kill them," Dr. Flores-Rozas says.
The MCG researchers suspect the genes may be protective from other stresses, such as a viral infection, as well.
They already are looking at their function and expression in cancer and cardiac cells normally and when exposed to doxorubicin.
Medical College of Georgia
Unfortunately, just as cancer treatment ends, heart problems can begin for some patients who get these drugs. Heart cells, called cardiomyocytes, can commit suicide, or apoptosis, says Dr. Ling Xia, a graduate student at the Department of Cardiology at China's Wuhan University who is part of an exchange program with MCG. The result is dilative cardiomyopathy, in which the heart becomes a boggy organ that can no longer pump blood out to the body. Damage can even show up years after treatment, she says noting there is no known way to prevent or treat it, short of a heart transplant.
The long-term goal of their research is prevention and maybe enhanced cancer treatment through development of ways to turn these genes off in cancer cells and on in heart cells, says Dr. Flores-Rozas, corresponding author on the study published in the Dec. 1 issue of Cancer Research. Dr. Xia is first author.
Another possibility is turning down their protection in cancer cells, which should necessitate less drug and result in less heart damage, says Dr. Flores-Rozas, noting that it's dose related and cumulative.
They did studies in relatively simple yeast cells from Dr. Anil Cashikar's yeast knockout collection. Yeast, which have about 6,000 genes compared to humans' 30,000, are good models for study of human cells because they include the same basic cellular functions such as replication, DNA repair, signaling and even cell death, says Dr. Cashikar, MCG geneticist and a study co-author.
They found 71 genes that conveyed varying degree of protection from doxorubicin. "The cell does not have a unique mechanism to protect from doxorubicin; it's a very complex response," says Dr. Flores-Rozas. "Some genes protect better than others. But in the absence of some of these genes, the cells will die from exposure to the drug."
The genes may even protect cancer and cardiac cells differently, he says noting one way doxorubicin stops cancer cells is by preventing their classic rapid division. Cardiac cells, on the other hand, don't divide. Still there's some common ground between the cells when it comes to protection. Cardiac cells have been known to use heat shock proteins to protect themselves from toxic injuries. This enables proteins made by cells to continue to function properly. "If you have activated heat shock response, you have more activate proteins," says Dr. Flores-Rozas. "If you have proteins that don't function, the cell is eventually going to die." The MCG researchers have shown the heat shock response also is activated in a stressed cancer cell.
He notes these newly identified protective genes likely already are expressed at some level before the cells are confronted with a stress such as a chemotherapeutic agent, then step up expression in response. "If it doesn't, doxorubicin will kill them," Dr. Flores-Rozas says.
The MCG researchers suspect the genes may be protective from other stresses, such as a viral infection, as well.
They already are looking at their function and expression in cancer and cardiac cells normally and when exposed to doxorubicin.
Medical College of Georgia
Doxorubicin News and Current Doxorubicin Events RSSCSHL scientists correlate enzyme expression levels with chemotherapy drug response
Why do cancer patients develop resistance to chemotherapy drugs, sometimes abruptly, after a period in which the drugs seem to be working well to reduce tumors or hold them in check? Although largely a mystery to scientists, the result when this occurs is all too familiar: patients relapse and in many cases die when their cancers become resistant.
McGill researchers overcome chemotherapy resistance in the lab
Researchers from McGill University's Faculty of Medicine have discovered a compound that reduces resistance to chemotherapy agents used to treat cancer. Their results were published in the June issue of The Journal of Clinical Investigation (JCI).
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.
Adding epratuzumab to standard therapy
Adding a second monoclonal antibody drug to chemotherapy looks promising for treatment of diffuse large B-cell lymphoma.
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.
New chemotherapy combo produces side effects, but no extra efficacy, in early breast cancer patients
Adding capecitabine, a drug that inhibits DNA synthesis and slows the growth of tumour tissue, to docetaxel, in patients with early breast cancer, leads to more toxicities and does not improve the efficacy of treatment.
NovoCure presents results from breast cancer pilot study
NovoCure announced today that it presented the results from a single-arm pilot trial evaluating the Novo-TTF, a non-invasive portable medical device, combined with neo-adjuvant chemotherapy for the treatment of patients with locally advanced breast cancer.
Scientists solve mystery of polyketide drug formation
Many top-selling drugs used to treat cancer and lower cholesterol are made from organic compounds called polyketides, which are found in nature but historically difficult for chemists to alter and reproduce in large quantities.
St. Jude study offers new hope for children with kidney tumors deemed inoperable
Physicians at St. Jude Children's Research Hospital have demonstrated that children with bilateral Wilms tumor, a cancer of the kidneys, can retain normal function in both kidneys by undergoing a procedure called bilateral nephron-sparing surgery, even when preoperative scans suggest that the tumors are inoperable.
Recurrent low-grade carcinoma of the ovary less responsive to chemo than more common ovarian cancers
Recurrent low-grade serous carcinoma, a rare type of ovarian cancer, is less sensitive to chemotherapy and therefore more difficult to treat than more common high-grade ovarian cancers, according to researchers from The University of Texas M. D. Anderson Cancer Center.
More Doxorubicin News Articles
| © 2008 BrightSurf.com |