Targeting prostate-specific membrane antigen in cancer therapy: can molecular medicine be brought to the surface?
Systemic chemotherapy can be associated with significant morbidity as a result of non-specific side effects and drug toxicity. A major advance in cancer therapy is the ability to target specific molecules and pathways due to increased knowledge of gene expression and biochemical function. In this issue of Cancer Biology & Therapy, a targeted approach to prostate cancer chemotherapy is explored using the inherent enzymatic activity of prostate-specific membrane antigen (PSMA) and peptide conjugated methotrexate. Substrate specificity and specific activity were determined using soluble PSMA while selective drug toxicity was determined using clonal inhibition of PSMA+ and PSMA- cancer cell lines. Peptide conjugates linked to methotrexate were identified with enhanced selective clonal inhibition in the presence of PSMA. Despite these promising results, multiple variables affecting clinical feasibility such as substrate stability and non-PSMA dependent drug uptake will require careful consideration before PSMA is ready for prime time as a selective chemotherapeutic target.
Leach
Fredrick
F
Scott Department of Urology, Baylor College of Medicine, Houston, Texas 77030, USA. fleach@bcm.tmc.edu
D000954:Antigens, Surface; D001224:Aspartic Acid / Q000378:metabolism; D016503:Drug Delivery Systems; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D011355:Prodrugs; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013379:Substrate Specificity
D000954:Antigens, Surface; D010446:Peptide Fragments; D011355:Prodrugs; D011993:Recombinant Fusion Proteins; D001224:Aspartic Acid; D018698:Glutamic Acid; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D008727:Methotrexate