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Altitude sickness drug helps overcome resistance to chemotherapy in the treatment of gliomas



The drug, acetazolamide, was investigated in a study published this month in Science Translational Medicine, which found that it helped to overcome resistance to chemotherapy drug temozolomide (TMZ). TMZ is frequently used in the treatment of gliomas, but some patients do not respond to the treatment. With the addition of acetazolamide, researchers identified an improvement in survival in pre-clinical models of glioma.

Study Details:

TMZ acts by damaging the DNA inside tumour cells, causing them to die. However, some tumour cells can block or repair this DNA damage, which limits the impact of chemotherapy. The study identified that the patients who were unresponsive to TMZ had high levels of a protein BCL-3. Researchers determined that this protein was responsible for shielding cancer cells from TMZ damage, by activating a protective enzyme called carbonic anhydrase II.

Acetazolamide is a carbonic anhydrase inhibitor. This makes the drug able to restore the ability of TMZ to kill tumour cells. The drug, sold under the trade name Diamox, is “cheap to make, easy to take and has limited side effects”, according to study director Professor Bahktiar Yamini from the University of Chicago. When taken in combination with TMZ, the drug resulted in a 30 to 40 per cent increase in survival in animal models.

"An important feature of predictors like BCL-3 is that they are informative," the authors note. "They can identify pathways to improve treatment response." By examining those pathways, the authors identified carbonic anhydrase inhibitors, such as acetazolamide, to reduce resistance to TMZ. 

This research is being fed into a phase 1 clinical trial, to examine the efficacy and safety of acetazolamide in combination with TMZ in humans. The trial will investigate the drug combination in patients with malignant astrocytoma, which will soon begin enrolling patients.

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