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Scientists at the temple University (USA) have developed a new method of treatment for immune to traditional therapy of cancerous tumors. Combination drug contributes to the accumulation of mutations in cancer cells. Article with results of a study published in the journal Cell Reports.
One of the causes of cancer are mutations in specific genes controlling the growth and reproduction of cells. These mutations can occur because of a decrease in the activity of proteins BRCA (eng. breast cancer), which restores the gaps in both DNA strands. However, tumors become prone to accumulate mutations, which eventually could promote the death of cancerous cells. It does not occur due to alternative mechanisms of repair (restoration) of DNA, such as enzymes PARP1 and PARP2. These molecules are very active in the tumors, remove single-stranded breaks, preventing the emergence of potentially lethal double-stranded breaks.
To treat tumors with BRCA deficiency use drug olaparib, which is an inhibitor of PARP. However, the treatment effect does not last long due to compensatory mechanisms resulting from mutations. Such mechanisms include the prevention of penetration of drug into the cell or its rapid removal from it, as well as activation of additional repair mechanisms, including protein RAD52. Scientists have put forward the hypothesis that simultaneous suppression of PARP and RAD52 is a more effective method of treatment.
Experiments with cell cultures showed that the inhibitor of RAD52 — 6-hydroxyl-DL-DOPA (derived antiparkinsonian funds levodopa) — suppresses the residual repair activity in cells with deficiency of BRCA-treated olaparib. Combined use of these drugs increased the accumulation of double-stranded breaks and inhibited the growth of adenocarcinoma cells. After 28 days of drug treatment cell with BRCA deficiency were completely dead. The same effect has been demonstrated in cell lines of leukemia and Burkitt’s lymphoma.
The new treatment was tested in a mouse model of chronic myeloid leukemia. Scientists have deduced transgenic mice, in which in the absence of tetracycline for about 70 days started to develop tumors with BRCA deficiency. In rodents that have been genetically suppressed the activity of either RAD52 or PARP, the disease appeared at 100-120 a day. However 33 percent of the animals who had both the inactive protein, for 200 days was not observed signs of disease.
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