title: 123I-MIP-1072, a small-molecule inhibitor of prostate-specific membrane antigen, is effective at monitoring tumor response to taxane therapy.
abstract: Because traditional endpoints in oncology trials are not always applicable for metastatic prostate cancer, better ways of following response to treatment are needed. Prostate-specific membrane antigen (PSMA) is a transmembrane protein expressed in normal human prostate epithelium and is upregulated in prostate cancer. (S)-2-(3-((S)-1-carboxy-5-((4-(123)I-iodobenzyl)amino)pentyl)ureido)pentanedioic acid, (123)I-MIP-1072, targets PSMA and was evaluated for monitoring the growth of PSMA-positive LNCaP cells in vitro and as xenografts after paclitaxel therapy.
  
  
  METHODS
  LNCaP and 22Rv1 cells were treated with paclitaxel (0-100 nM) for 48 h, after which binding of (123)I-MIP-1072 was examined. Cell number was determined by MTS assay, and PSMA expression was analyzed by Western blotting. LNCaP xenograft-bearing mice were treated with paclitaxel (6.25 mg/kg) for 3.5 cycles of 5 d on and 2 d off. Tissue distribution of (123)I-MIP-1072 was determined on days 2 and 23 from the start of paclitaxel treatment.
  
  
  RESULTS
  Paclitaxel (10-100 nM) inhibited LNCaP and 22Rv1 cell growth after 48 h, and binding of (123)I-MIP-1072 was proportional to cell number. Western blot analysis verified there was no paclitaxel-dependent change in PSMA expression. Treatment of LNCaP xenografts with paclitaxel resulted in a decrease in tumor volume (-21%), compared with an increase in the untreated xenografts (+205%) by day 23. Tumor uptake of (123)I-MIP-1072 was proportional to changes in tumor mass: decreased by paclitaxel treatment and increased in untreated mice.
  
  
  CONCLUSIONS
  Treatment of LNCaP cells or xenograft tumors with paclitaxel resulted in growth inhibition, which was detected with (123)I-MIP-1072. The high specificity of (123)I-MIP-1072 for prostate cancer may allow monitoring of tumor progression in patients before, during, and after chemotherapy.
authors.affiliation: Molecular Insight Pharmaceuticals, Cambridge, Massachusetts 02142, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Hillier
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Kern
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Maresca
authors.forename: John C
authors.initials: JC
authors.lastname: Marquis
authors.forename: William C
authors.initials: WC
authors.lastname: Eckelman
authors.forename: John L
authors.initials: JL
authors.lastname: Joyal
authors.forename: John W
authors.initials: JW
authors.lastname: Babich
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005971:Glutamates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D051379:Mice; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C544833:2-(3-(1-carboxy-5-(4-iodobenzylamino)pentyl)ureido)pentanedioic acid; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D005971:Glutamates; D007457:Iodine Radioisotopes; D014508:Urea; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D017239:Paclitaxel