title: Preliminary evaluation of prostate-targeted radiotherapy using (131) I-MIP-1095 in combination with radiosensitising chemotherapeutic drugs.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  These results indicate that targeted radiotherapy of prostate cancer may be optimised by combining its administration with chemotherapy.
authors.affiliation: Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Mathias
authors.initials: M
authors.lastname: Tesson
authors.affiliation: Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Rae
authors.affiliation: Beatson Institute for Cancer Research, Glasgow, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Nixon
authors.affiliation: Division of Radiopharmacy, Department of Radiology, Cornell University, New York, NY, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Babich
authors.affiliation: Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mairs
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D000069286:Bortezomib / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004221:Disulfiram / Q000494:pharmacology; D005971:Glutamates / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D058990:Molecular Targeted Therapy / Q000379:methods*; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D018874:Spheroids, Cellular / Q000187:drug effects; D013876:Thiophenes / Q000494:pharmacology; D019772:Topotecan / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014508:Urea / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C544834:2-(3-(1-carboxy-5-(3-(4-iodobphenyl)ureido)pentyl)ureido)pentanedioic acid; C532363:3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide; D000970:Antineoplastic Agents; D005971:Glutamates; D007093:Imidazoles; D007457:Iodine Radioisotopes; D010793:Phthalazines; D010879:Piperazines; D013876:Thiophenes; C482205:nutlin 3; D000069286:Bortezomib; D019772:Topotecan; D014508:Urea; D004221:Disulfiram; C531550:olaparib
keywords: prostate-specific membrane antigen; radiopharmaceutical; radiosensitisation; spheroids