Multicellular Complex Tumor Spheroid Response to DNA Repair Inhibitors in Combination with DNA-damaging Drugs
Multicellular spheroids made up of malignant cells, endothelial cells, and mesenchymal stem cells offered being an in vitro type of human solid tumors to research the potentiation of DNA-damaging drugs by pharmacologic modulation of DNA repair pathways. The DNA-damaging drugs, topotecan, trabectedin, and temozolomide were coupled with varied inhibitors of DNA damage response enzymes including PARP (olaparib or talazoparib), ATM (ataxia telangiectasia mutated AZD-1390), ATR (ataxia telangiectasia and Rad3-related protein berzosertib or elimusertib), and DNA-PK (DNA-dependent protein kinase nedisertib or VX-984). A variety of clinically achievable concentrations were tested to the clinical Cmax, if known. Mechanistically, the kinds of DNA damage caused by temozolomide, topotecan, and trabectedin are distinct, that was apparent in the response of spheroids to combinations with assorted DNA repair inhibitors. Although most combinations led to additive cytotoxicity, synergistic activity was observed for temozolomide coupled with PARP inhibitors in addition to mixtures of the ATM inhibitor AZD-1390 with either topotecan or trabectedin. These bits of information might provide guidance for selecting anticancer agent combinations AZD1390 worth further analysis.