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About Sickkids
About SickKids

February 22, 2008

SickKids Scientists discover potential therapeutic agent for cancer

Scientists at The Hospital for Sick Children (Sickkids) have made an important research discovery which may influence the way that chemotherapy is delivered in certain types of cancer. The discovery is highlighted in a research paper, entitled “ Inhibition of Multidrug Resistance 1 (MDR1) by AdamantylGb3, a globotriaosylceramide analog ”, published in today's issue of the Journal of Biological Chemistry (JBC).

One of the major difficulties in cancer chemotherapy is that over time, cells become resistant to many anticancer drugs. Cells respond to these drugs by making a molecule called MDR1 (Multidrug Resistance 1) and then transporting it to the surface of the cell, where it acts like a pump, removing these drugs from the cells and reducing their effectiveness. As a result, higher doses of these chemotherapeutic agents are required in order to have an effect on the cancer and these increased doses can cause significant side effects in patients. Recently, Dr. Clifford Lingwood, Senior Scientist in the Molecular Structure & Function program at SickKids Research Institute and his team discovered a compound, called adamantylGb3 (adaGb3), which they have shown to prevent MDR1 from reaching the surface of the cell, potentially making cancer cells once again susceptible to chemotherapy.

Using a combination of cell biology techniques, Lingwood's team demonstrated that adaGb3 works to sequester MDR1 inside the cell and away from the cell surface. The adaGb3 compound was also shown to increase the effectiveness of the anticancer drug vinblastine - a drug susceptible to MDR1 - in killing cultured cells. Importantly, adaGb3 was seen to stop vinblastine from being pumped out of cells derived from the gut lining. As MDR1 is expressed on cells in the lining of the gut and in the blood-brain barrier, adaGb3 may have the potential to increase the “bioavailability” of MDR1 susceptible drugs increasing the amount that gets into either the body or the brain.

“This is a good starting point to develop a new family of drugs, which will improve the bioavailability and effect of the chemotherapy drugs,” said Lingwood. He also pointed out that these results may potentially impact treatment of lysosomal storage diseases such as Tay-Sachs, Gauchers and Fabry disease, by specifically interfering with the glycolipid synthesis pathways in the cell. “As well, this type of inhibitor may potentially improve the bioavailability of other types of drugs, specifically those that need to pass through the intestine or into the brain.”

Lingwood previously demonstrated that adaGb3 also inhibits HIV infection. His group is continuing their studies of the molecular basis of MDR1 function, specifically with regard to the interaction of MDR1 with Gb3, and the disruption of this interaction by adaGb3. They are making subtle structural changes to the molecules to discover how small changes in the molecules are related to binding and their function.

For more information, please contact:

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