Preliminary evaluation of prostate-targeted radiotherapy using 131I-MIP-1095 in combination with radiosensitising chemotherapeutic drugs†

Abstract

Abstract Objectives Despite recent advances in the treatment of metastatic prostate cancer, survival rates are low and treatment options are limited to chemotherapy and hormonal therapy. 131I-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 131I-MIP-1095 with cytotoxic drug treatments. Methods Various cytotoxic agents were evaluated in combination with 131I-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. Key findings 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 131I-MIP-1095. However, the Chk1 inhibitor AZD7762 failed to potentiate the effect of 131I-MIP-1095. Conclusions These results indicate that targeted radiotherapy of prostate cancer may be optimised by combining its administration with chemotherapy.