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To release chemoresistance in cancer



Cancer

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Associate Professor Hamsa Puthalakath, a researcher at La Trobe University, is the first scientist to have pierced a mystery that has long been explaining why some cancers do not respond to treatment with one of the most effective chemotherapy drugs : 5-Fluorouracil (5-FU).

"We are currently working on the development of a drug that will make 5-FU effective in previously resistant cancers," said Associate Professor Puthalakath.

The research could also lead to a laboratory test to check for resistance to 5-FU, thereby reducing unnecessary chemotherapy treatments.

5-FU (trade name Adrucil / Carac / Efudex) is on the Model List of Essential Medicines of the World Health Organization. It is used to fight colorectal, breast, head, neck and digestive aero-digestive cancers, but acquired resistance in response to treatment is a major problem and nearly half of patients with colorectal cancer with metastases become resistant to 5-FU.

In an article published today in the Proceedings of the National Academy of Sciences (PNASAssociate Professor Puthalakath explains for the first time the precise mechanism by which cancer develops resistance to 5-FU.

It binds resistance to 5-FU to a little known protein called "BOK". Associate Professor Puthalakath said scientists have been questioning the function of the BOK for decades, with many claiming that the function was redundant.

"I've always thought that nature was keeping proteins for a reason," said Associate Professor Puthalakath. "Our research shows that BOK binds to an enzyme called UMPS, enhancing the cell's proliferative capacity.Because of BOK, cells have trouble synthesizing DNA and can not proliferate." The same enzyme is also responsible for the conversion of 5-FU into its toxic form Therefore, to avoid the toxicity of 5-FU, cancer cells deactivate BOK. "

The cancer cells then become dormant and absorb less than 5-FU, allowing them to survive chemotherapy before mutating to become even more aggressive.

The research of Associate Professor Puthalakath, funded by the University of La Trobe (FRG) and the Swiss National Fund for Scientific Research, has allowed testing of samples of patients with cancer. He discovered that patients who had responded to 5-FU treatment had a BOK, while those who had not responded to chemotherapy did not have BOK.

"This shows that in the absence of the BOK, there is no point in trying to use 5-FU as an effective chemotherapy treatment," said the associate. Puthalakath.

"By understanding the scientific basis of resistance to chemotherapy, we believe we have found the" Achilles' heel "of cancer, which has important implications for the future development of drugs."


Prolonged Exposure to a Protein Inhibitor Could Be the Key to More Effective Chemotherapy Against Cancer


More information:
Rahul Srivastava et al., "BCL-2 family BOK protein is a positive regulator of uridine metabolism in mammals" PNAS (2019). www.pnas.org/cgi/doi/10.1073/pnas.1904523116

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La Trobe University




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To release chemoresistance in cancer (July 15, 2019)
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