Update: 16.07.2008
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).
Dr. Jerry Pelletier, PhD candidate Marie-Eve Bordeleau, and post-doctoral fellow Francis Robert, of the Department of Biochemistry and the McGill Cancer Centre – along with colleagues from Boston University, the Sloan-Kettering Cancer Center, the University of Vienna and the Howard Hughes Medical Institute – conducted an extensive study on a class of natural products known as cyclopenta benzofuran flavaglines (CBF).
Working with mice genetically modified to mimic human leukaemia, they discovered that one particular CBF compound, silvestrol, can effectively re-sensitize tumours to chemotherapy, making them susceptible to the killing effects of anticancer drugs.
“One of the major problems with cancer therapy is that the tumours either fail to respond or stop responding over time to various chemotherapy drugs,” Pelletier said. “One reasonable explanation for why this happens is the normal process of protein synthesis in the cell is usurped, principally because cancer cells grow faster and have higher metabolic needs. The normal checks and balances are no longer present.”
Pelletier’s lab at the Department of Biochemistry and McGill Cancer Centre focuses on high-throughput assays of various compounds to determine their anti-cancer effectiveness. One that showed promise was silvestrol, a natural compound derived from Aglaia silvestris, a large genus of trees and shrubs found in Malaysia, South China and some Pacific islands. It has been used in Malaysian folk medicine for generations, but never as a cancer therapy.
“We made a conscious decision early on in our research to also screen for natural products,” Pelletier says. “Silvestrol is not a synthetic compound you can buy from commercial suppliers.”
In the lab, Pelletier explained, silvestrol therapy re-sensitized leukaemia cells which had already demonstrated resistance to the chemotherapy agent doxorubicin.
“Essentially, we have turned off the cancer cell’s survival signals, which is associated with resistance,” he said.
However, he cautioned, though synthetic silvestrol is now starting to become available, trials in humans and possible treatments are still many years away.
(Source: The Journal of Clinical Investigation: McGill University: July 2008)
Chemotherapy uses powerful anticancer drugs that travel through the bloodstream, making it potentially useful for cancers that have spread. Oncologists use about 50 different chemotherapeutic drugs to combat cancer, generally administering more than one drug at a time because these drugs are more powerful when combined. Taken orally or injected into the bloodstream, chemotherapeutic drugs interfere with cancer cells’ ability to make new DNA or divide properly. In some cases, the drugs cause programmed cell death.
Many leukemias and lymphomas and cancer of the testicles are successfully treated with chemotherapy. Breast, lung, colorectal, and prostate cancer are not currently curable with chemotherapy alone, so chemotherapy is often used in combination with other therapies. In fact, the most common combination of cancer treatments is surgery or radiation therapy followed by chemotherapy.
Chemotherapy often causes severe side effects, particularly reduced resistance to infection, internal bleeding, diarrhea, nausea, vomiting, hair loss, and insufficient oxygen in the blood, known as anemia. Some tumors develop resistance to many drugs after exposure to just one drug, a condition called multidrug resistance. When this happens, there may be no drugs that are effective against the tumor.
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