Cancer inhibitors
Siberian cancer inhibitors are undergoing preclinical trials
Scientists of the Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk Institute of Organic Chemistry named after N. N. Vorozhtsov SB RAS and the Institute of Cytology and Genetics SB RAS have found effective protein targets for the development of drugs against cancer of the rectum, lungs and intestines. Now these compounds are at the stage of preclinical testing.
"Many of the drugs used today for the treatment of oncology (some anti-cancer drugs, radiotherapy, etc.) are based on damage to the DNA of tumor cells. However, DNA repair systems are very effective in repairing the damaged DNA structure, hence they will resist any DNA damage. This requires increasing the doses of drugs and radiation in radiotherapy and leads to serious consequences for the patient's body. In addition, there is an unpleasant paradox: in cancer cells (and especially in metastatic cells), repair systems often work even more efficiently than in normal ones. Therefore, knowledge about the work of repair enzymes is very important for the development of drugs," says Olga Ivanovna Lavrik, Head of the Laboratory of Bioorganic Chemistry of enzymes of the IHBFM SB RAS, Corresponding Member of the RAS.
One of the main factors that regulate repair in humans and higher organisms are poly(ADP-ribose)-polymerases (PARP) (enzymes that catalyze poly-ADP-ribosylation, one of the types of posttranslational modification of proteins. – Ed.). Recently, the drug "Olaparib" was created – the first PARP1 inhibitor introduced into clinical practice. The FDA (U.S. Food and Drug Administration) has approved the use of this drug for the treatment of ovarian and breast cancer in women with a mutation in the BRCA1 and BRCA 2 genes. The drug is in the third stage of clinical trials for the treatment of other types of cancer.
"However, these inhibitors are used only in the second line of therapy, and it is in patients who have certain mutations. Therefore, we need to look at other targets," the researcher comments. – We are conducting a search and preclinical trials of anticancer drugs that inhibit other key DNA repair enzymes. They can increase the sensitivity of tumors to therapy and reduce the number and severity of side effects. Tests of these drugs on mice showed a 50% reduction in the primary tumor and 90% reduction in metastases."
For example, the use of a tyrosyl-DNA phosphodiesterase 1 inhibitor (Tdp1) in combination with topotecan (a cytostatic drug from the camptothecin group. – Ed.) reduces the weight of the tumor by 30-50%, and the number of metastases in the lungs decreases by five times. The effect of the inhibitor is noticeable already on the second or third day after the start of treatment and increases in the future.
Olga Lavrik noted that all these studies were carried out in Novosibirsk, where there are optimal conditions to create trial compounds, conduct computer modeling, counter synthesis, in vitro and animal testing.
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