title: Pharmacokinetics and toxicology of a fibroblast activation protein (FAP)-activated prodrug in murine xenograft models of human cancer.
abstract: BACKGROUND
  As carcinoma progresses, the stroma undergoes a variety of phenotypic changes, including the presence of carcinoma-associated fibroblasts (CAFs) that express fibroblast activation protein (FAP). FAP is a post-prolyl endopeptidase whose expression in a healthy adult is largely restricted to the cancer-associated stroma. FAP-targeted prodrugs with a 100-fold greater therapeutic window over the parent compound were previously generated.
  
  
  METHODS
  Prodrugs and non-cleavable controls were incubated in the presence of FAP. Plasma and tumor half-lives (t1/2) of the full-length and active forms of the prodrugs were determined using LCMS. Biodistribution studies of prodrug activation were performed. Histopathological analysis of tissues from treated animals were compared to vehicle-treated controls. Toxicity and efficacy studies were performed in human breast (MDA-MB-231 and MCF-7) and prostate (LNCaP) cancer xenografts models.
  
  
  RESULTS
  These FAP-activated prodrugs have a significantly slower clearance from tumor tissue than the circulation (∼12 vs. ∼4.5 hr). Micromolar concentrations of active drug persist in the tumor. Active drug is detected in non-target tissues; however, histopathologic evaluation reveals no evidence of drug-induced toxicity. A FAP-activated prodrug (ERGETGP-S12ADT) inhibits tumor growth in multiple human breast and prostate cancer xenograft models. The anti-tumor effect is comparable to that observed with docetaxel, but results in significantly less toxicity.
  
  
  CONCLUSIONS
  FAP-activated prodrugs are a viable strategy for the management of prostate and other cancers. These prodrugs exhibit less toxicity than a commonly used chemotherapeutic agent. Further refinement of the FAP cleavage site for greater specificity may reduce prodrug activation in non-target tissues and enhance clinical benefit.
authors: Chemical Therapeutics Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: W Nathaniel
authors: WN
authors: Brennen
authors: D Marc
authors: DM
authors: Rosen
authors: Alcides
authors: A
authors: Chaux
authors: George J
authors: GJ
authors: Netto
authors: John T
authors: JT
authors: Isaacs
authors: Samuel R
authors: SR
authors: Denmeade
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010450:Endopeptidases; D018093:Gelatinases / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051379:Mice; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012697:Serine Endopeptidases / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D000970:Antineoplastic Agents; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D011355:Prodrugs; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha
keywords: carcinoma-associated fibroblast (CAF); fibroblast activation protein (FAP); pharmacokinetics; prodrug