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    Breakthrough Research Offers Solutions to Minimize Side Effects of Breast and Ovarian Cancer Treatments

    A new research has found Cancer Treatments ways to reduce the side effects of breast and ovarian cancer treatment. The research was published in the journal Nature.

    Cancer Treatments anti-cancer medications also target healthy cells in addition to malignant cells. Their use may become restricted if their effects on the latter are excessively powerful. The mechanism of action of PARP inhibitors, which are specifically used for treating breast and ovarian cancer in individuals with the BRCA gene mutation, has been determined by a team from the University of Geneva (UNIGE) in cooperation with Basel-based FoRx Therapeutics. These inhibitors prevent the PARP proteins from engaging in two distinct functions. Healthy cells are protected while the harmful effect on cancer cells is maintained by inhibiting one of them.

    The mechanism of action of PARP inhibitors, which are specifically used for treating breast and ovarian cancer in individuals with the BRCA gene mutation, has been determined by a team from the University of Geneva (UNIGE) in cooperation with Basel-based FoRx Therapeutics. (Shutterstock)
    The mechanism of action of PARP inhibitors, which are specifically used for treating breast and ovarian cancer in individuals with the BRCA gene mutation, has been determined by a team from the University of Geneva (UNIGE) in cooperation with Basel-based FoRx Therapeutics. (Shutterstock)

    The effectiveness of these treatments will be enhanced by this research, which was published in the journal Nature.

    Despite the thousands of lesions that damage our DNA every day, the genome of our cells is particularly stable thanks to a highly efficient repair system. Among the genes coding for repair proteins are BRCA1 and BRCA2 (for Breast Cancer 1 and 2), which are particularly involved in DNA double helix breaks. The presence of mutations in these genes (in around 2 out of every 1,000 women) can result in non-repair of damaged DNA, and greatly increase the risk of developing breast or ovarian cancer (or prostate cancer in men).

    PARP inhibitors have been used to treat this type of cancer for around 15 years. PARP proteins can detect breaks or abnormal structures in the DNA double helix. PARPs then temporarily stick to the DNA, synthesizing a chain of sugars which acts as an alarm signal to recruit the proteins involved in DNA repair. Treatments based on PARP inhibitors block these activities and trap the PARP protein on the DNA. There is then no alarm signal to trigger DNA repair.

    This treatment proves toxic for fast-growing cells such as cancer cells, which generate too many mutations without having time to repair them and are thus doomed to die. But our bodies are also home to fast-growing healthy cells. This is the case, for example, of hematopoietic cells – the source of red and white blood cells – which, as collateral victims, are also massively destroyed by anti-PARP treatments.

    ”We discovered that PARP not only acts as an alarm signal to recruit DNA repair proteins, it also intervenes when abnormal DNA structures are formed as a result of collisions between different machineries that read or copy the same portion of DNA,” explains Michalis Petropoulos, post-doctoral fellow in the Department of Molecular and Cellular Biology at the UNIGE Faculty of Science and first author of the study.

    ”We therefore discovered that inhibition of the enzyme activity is sufficient to kill cancer cells, whereas trapping – when PARP is strongly bound to DNA – kills the normal cells as well, and therefore is responsible for the toxicity of these drugs. This knowledge will make it possible to develop safer PARP inhibitors that inhibit PARP’s enzymatic activity without trapping it on DNA,” summarizes Thanos Halazonetis, head of the study.

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