1/3/2023 0 Comments Calcusyn synergism![]() ![]() Olaparib was the most active PARP1 inhibitor to combine with trabectedin and we confirmed the antitumor and antimetastatic activity of trabectedin/olaparib combination in mice models. Trabectedin activated PARP1 enzyme and the combination with PARP1 inhibitors potentiated DNA damage, cell cycle arrest at G2/M checkpoint and apoptosis, if compared to single agents. We searched for key determinants of drug synergism by comparative genomic hybridization (aCGH) and gene expression profiling (GEP) and validated their functional role. We investigated trabectedin and PARP1 inhibitor synergism in several tumor histotypes both in vitro and in vivo (subcutaneous and orthotopic tumor xenografts in mice). We hypothesized that PARP1 targeting could perpetuate trabectedin-induced DNA damage in tumor cells leading finally to cell death. These kinds of damage lead to the activation of PARP1, a first-line enzyme in DNA-damage response pathways. It binds to minor groove of DNA inducing single- and double-strand-breaks. Trabectedin is an isoquinoline alkylating agent with a peculiar mechanism of action. Enhancing the antitumor activity of the DNA-damaging drugs is an attractive strategy to improve current treatment options. ![]()
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January 2023
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