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Enzyme inhibitor in combination with chemotherapy slows the growth of glioblastomas

January 24, 2018 13:31

Study investigated the possibility of using a new combination of chemotherapy drugs in the treatment of glioblastoma.

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In animal experiments, human glioblastoma significantly regressed in the treatment of a combination of experimental inhibitor and temozolomide enzymes used in chemotherapy.

Regression observed in the combination therapy of temozolomide and inhibitor SLC-0111, which is aimed at the enzyme carbonic anhydrase 9 or CA9, was greater than if we use only SLC-0111 or temozolomide alone, says study leader Anita Helmeland, assistant professor of cellular, developmental and integrative biology at the University of Alabama at Birmingham.

"Our experiments clearly show that the strategy of targeting carbonic anhydrase, which increases in glioblastoma, CA9, will improve the effectiveness of temozolomide" - Helmeland said. "We believe that the combination of drugs can improve the results terapiimy sensitive to chemotherapy."

Glioblastoma is the most common primary brain tumor in adults observed. Half tumors recur after at least seven months after the passage of the standard treatment of brain tumors - operation temozolomide and radiation. Median survival after diagnosis of this deadly cancer is between 12 and 14 months. Thus, an urgent need for new approaches to therapy.

Solid tumors such as glioblastoma, create a microenvironment in and around itself. The general condition is hypoxia, lack of oxygen, because the tumor cells into the blood. They produce energy through glycolysis, the metabolic method that does not require oxygen. Glycolysis, in turn, alters the acid-base balance in the tumor - the extracellular space becomes more acidic, and the interference of tumor cells becomes more alkaline, adapting to this change.

Faced with this hypoxia and oxidative stress tumor cells overproduce CA9, a membrane enzyme that converts carbon dioxide and water to bicarbonate and protons. This reaction helps to maintain the change in the acid-base balance in the tumor microenvironment.

Thus, CA9 is a possible therapeutic target, and SLC-0111 inhibitor exhibits a more than 100-fold specificity against CA9 compared with two other forms of carbon dioxide anhydrides, CA1 or CA2. In addition, members of this project have previously shown that SLC-0111 shows efficacy against xenografts of breast cancer in animals. SLC-0111 was tested in a Phase I clinical trial I, sponsored Welichem Biotech Inc. in Canada for patients with advanced solid tumors.

Study Group glioma cells were examined in a cell culture, which were obtained from aggressive pediatric glioblastoma primary and recurrent tumors from adult patient. They studied tumor in mice using recurrent glioblastoma in adults.

One reason is relapse glioblastoma glioma therapeutically resistant subpopulation of cells, known as cells, initiating a brain tumor. The purpose of the exercise was to look at the effect of combination therapy on many glioblastoma cells.

The researchers found that the combined treatment with temozolomide and SLC-0111 in experiments on cell cultures:

  • reduces cell growth of glioblastoma.
  • stop cell division induced cell cycle by creating breaks in DNA.
  • shift tumor metabolism and intracellular acid-base balance by reducing metabolic intermediates.
  • inhibited cell enrichment, triggering a brain tumor.

"Clinical trials often begin with glioblastoma patients with recurrent tumors, and we have demonstrated efficacy for SLC-0111 with temozolomide in recurrent glioblastoma," - the researchers write. "Therefore, our data strongly suggest the translational potential of SLC-0111 for the treatment of brain tumors."



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