Multicellular Complex Tumor Spheroid Response to DNA Repair Inhibitors in Combination with DNA-damaging Drugs.

ABSTRACT: Multicellular spheroids comprised of malignant cells, endothelial cells, and mesenchymal stem cells served as an in vitro model of human solid tumors to investigate the potentiation of DNA-damaging drugs by pharmacologic modulation of DNA repair pathways. The DNA-damaging drugs, topotecan, trabectedin, and temozolomide were combined 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 range of clinically achievable concentrations were tested up to the clinical C_max, if known. Mechanistically, the types of DNA damage induced by tem

SUBMITTER: Dexheimer TS 

PROVIDER: S-EPMC10452929 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature