Abstract
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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 < 0.001) for the combination. Cell cycle analysis demonstrated that DSF:Cu decreased the G2 population from 25.7% to 18.67% (P < 0.01) after γ-irradiation from a Cobalt-60 source. Synergism between DSF:Cu and γ-irradiation was also demonstrated in SK-N-BE(2c) (neuroblastoma) and UVW (glioma) cell lines by clonogenic assay in conjunction with isobologram and combination index (CI) analyses. The CI values for combination treatment were 0.71 ± 0.11 and 0.76 ± 0.13, respectively, indicative of supra-additive clonogenic cell kill.
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.