Enhancement of prostate-targeted radiotherapy using [131I]MIP-1095 in combination with radiosensitizing chemotherapeutic drugs

119 Objectives The prostate specific membrane antigen (PSMA)-targeting small molecule radiopharmaceutical, MIP-1095 (J Med Chem.2009,22;52(2):347-57), was radiolabelled with I-131 and was evaluated pre-clinically. Growth delay of spheroids derived from LNCaP prostate carcinoma cells was used to determine the radiosensitizing potential of various chemotherapeutic drugs in combination with [131I]MIP-1095. Methods Enhanced efficacy was manifest by a statistically significant reduction of the area under the volume/time growth curve (AUC) resulting from combination treatment compared with that achieved by either agent alone. Various chemotherapeutic drugs were investigated for synergistic interaction: olaparib (PARP-1 inhibitor), topotecan (topoisomerase I inhibitor), docetaxel (mitotic spindle-targeting agent), nutlin-3 (inhibitor of the P53-MDM2 interaction) and DSF:Cu (the copper-chelated form of disulfiram). Results DSF:Cu showed the greatest radiosensitizing effect, indicated by AUC values of 34.59 ± 1.00 for control, 23.53 ± 1.10 for [131I]MIP-1095, 22.71 ± 1.85 for DSF:Cu and -5.55 ± 1.76 ( P Conclusions These results demonstrated that DSF:Cu enhanced the efficacy not only of external beam radiation but also of targeted radionuclide therapy. The suggested radiosensitizing mechanism is inhibition of radiation-induced G2 arrest. Therefore DSF:Cu may have anti-cancer potential in combination with radiotherapy.