PROSTATE-SPECIFIC MEMBRANE ANTIGEN: PRESENT AND FUTURE APPLICATIONS SAM S. CHANG, PAUL B. GAUDIN, VICTOR E. REUTER, AND WARREN D. W. HESTON P rostate-specific membrane antigen (PSMA) is an approximately 100-kDa type II membrane protein originally characterized by the monoclonal antibody (mAb) 7E11 and expressed in all types of prostatic tissue, including benign epithelium, be- nign prostatic hyperplasia, prostatic intraepithelial neoplasia, and carcinoma. 1–5 Its expression has been studied on the mRNA transcript level with the RNAse protection assay and on the protein level by Western blot analysis and immunohistochemistry. The gene for PSMA has been fully sequenced and cloned 6 and encodes for a protein with a three-part structure: a 19 amino acid internal portion, a 24 amino acid transmembrane portion, and a 707 amino acid external portion. Two groups have in- dependently confirmed PSMA’s genetic location on the short arm of chromosome 11. 7,8 Two variations of the PSMA protein, designated as PSMA and the spliced variant PSM', have been characterized, but their individual roles have not been definitively elucidated. 9,10 PSM' lacks 266 nucleotides near the 5' amino terminus and, as a result, does not have a transmembrane portion and exists in the cell cyto- plasm. PSMA is the predominant form in cancer; PSM' predominates in the benign prostate. 10 Different strategies involving PSMA are being ex- plored for both the diagnosis and treatment of prostate cancer, and many appear promising. These include radiographic examinations, serum PSMA measurements, and immunotherapy trials. PSMA’s role, however, continues to expand, as re- cent studies have demonstrated that PSMA selec- tively reacts with tumor-associated angiogenic neovasculature in many different malignancies. This report briefly characterizes PSMA and dis- cusses its present and future diagnostic and thera- peutic applications. PSMA FUNCTIONS FOLATE HYDROLASE PSMA has a unique folate hydrolase activity ini- tially discovered in PSMA-expressing LNCaP cells. Pinto et al. 11 demonstrated that LNCaP cells have the ability to remove the gamma-linked terminal glutamates from folate in a sequential fashion. In animal studies, pig intestinal carboxypeptidase cDNA shares high sequence homology with hu- man PSMA, and this finding suggests that the folate hydrolase in human duodenal intestine in fact rep- resents the PSMA protein or a very similar pro- tein. 12 PSMA’s novel folate hydrolase ability makes it uniquely attractive for a prodrug activation strat- egy. NEUROCARBOXYPEPTIDASE PSMA also simulates the activity of a rat brain neurocarboxypeptidase. Work by Carter et al. 13 identified a partial cDNA sequence from a protein of the rat brain that had an 86% homology with a region of the PSMA gene. Studying PSMA-positive LNCaP cells, this group found that LNCaP cells expressed the same enzymatic activity as the rat brain enzymatic protein. This rat brain enzyme was a neurocarboxypeptidase that cleaves alpha-linked glutamates from N-acetylaspartylglutamate. 13 This same group has characterized the N-acetylated al- pha-linked acidic dipeptidase in the human brain and have concluded that this neuropeptidase is very likely to be PSMA. 14 In the human prostate are a significant number of neuroendocrine and secre- tory cells, but the specific function of PSMA is cur- rently unknown and warrants further research. ANTI-PSMA ANTIBODIES Initially, the mAb 7E11 was the only available anti-PSMA mAb to examine PSMA expression. The 7E11 mAb binds a six amino acid intracellular epitope of PSMA near the amino terminus, and this This study was supported in part by grants from the National Institutes of Health (DK/CA 47650) and from the Koch and CaPCure Foundations. From the Departments of Urology and Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York W.D.W. Heston is currently at the Department of Urology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. Reprint requests: Sam S. Chang, M.D., Department of Urology, 10th Floor, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021 Submitted: October 21, 1999, accepted (with revisions): No- vember 23, 1999 REVIEW © 2000, ELSEVIER SCIENCE INC. UROLOGY 55: 622– 629, 2000 • 0090-4295/00/$20.00 622 ALL RIGHTS RESERVED PII S0090-4295(99)00600-7