nutlin-3a and olaparib

Despite recent advances in the treatment of metastatic prostate cancer, survival rates are low and treatment options are limited to chemotherapy and hormonal therapy. (131) I-MIP-1095 is a recently developed prostate-specific membrane antigen (PSMA)-targeting, small molecular weight radiopharmaceutical which has anti-tumour activity as a single agent. Our purpose was to determine in vitro the potential benefit to be gained by combining (131) I-MIP-1095 with cytotoxic drug treatments.. Various cytotoxic agents were evaluated in combination with (131) I-MIP-1095 for their capacity to delay the growth of LNCaP cells cultured as multicellular tumour spheroids. Two end-points were used to assess treatment efficacy: (i) the time required for doubling of spheroid volume and (ii) the area under the volume-time growth curves.. The PARP-1 inhibitor olaparib, the topoisomerase I inhibitor topotecan, the proteasome inhibitor bortezomib, the inhibitor of the P53-MDM2 interaction nutlin-3 and the copper-chelated form of the oxidising agent disulfiram (DSF:Cu) all significantly enhanced the inhibition of the growth of spheroids induced by (131) I-MIP-1095. However, the Chk1 inhibitor AZD7762 failed to potentiate the effect of (131) I-MIP-1095.. These results indicate that targeted radiotherapy of prostate cancer may be optimised by combining its administration with chemotherapy.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Cell Line, Tumor; Cell Proliferation; Disulfiram; Glutamates; Humans; Imidazoles; Iodine Radioisotopes; Male; Molecular Targeted Therapy; Phthalazines; Piperazines; Prostate; Spheroids, Cellular; Thiophenes; Topotecan; Tumor Cells, Cultured; Urea