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Prostate specific membrane antigen (PSMA) is a folate gamma glutamyl carboxypeptidase that is oriented on the plasma membrane of normal and prostate cancer cells. A cytosolic version of PSMA, PSM', results from alternative splicing of the PSMA gene. Two additional alternatively spliced variants of PSMA, PSM-C and PSM-D, have been described recently. The ratio of PSMA to PSM' mRNA was higher in a small number of prostate cancer specimens compared to normal prostate cancer and benign prostatic hypertrophy (Su et al. Cancer Res 1995;55:1441). The intent of our study was to measure the gene expression of PSMA and the 3 PSMA splice variants in a large number of patient's tissues. A real-time, quantitative PCR assay was developed to quantify PSMA, PSM', PSM-C and PSM-D. Discrimination among the variants was achieved by designing unique primers and TaqMan probes for each gene. Amplification and detection was specific for the desired splice variant and was sensitive to one gene copy per reaction. The assay was used to quantify the gene expression in specimens of normal, benign, primary and metastatic prostate cancer from 72 patients. The mean PSMA expression (relative to 18S rRNA) was 2- to 3-fold lower in normal prostate (n = 4) compared to primary (n = 55, p = 0.31) and metastatic (n = 20, p = 0.33) prostate cancer. There was no difference in the PSMA expression between benign and cancerous prostate tissue from the same patients (n = 35). The ratio of PSMA to PSM' was lowest in the normal prostate and increased with increasing Gleason score (p < 0.001). The increased ratio in these tissues was a reflection of both increasing PSMA levels and decreasing PSM' mRNA. The expression of PSM-C did not differ in any of the tissue categories studied. The expression of PSM-D was similar in normal and primary prostate cancer but was 2-fold higher in lymph node (p < 0.005) and bone metastases (p < 0.05) compared to the primary tumors. Our results of the first detailed quantitative analysis of PSMA mRNA expression in patient's tissues demonstrate that PSMA and the 3 PSMA splice variants are expressed in normal, benign, cancerous and metastatic prostate cancer. We note increased PSMA expression in some malignant tissues, however, these increases are modest in magnitude. We also report that the expression of a novel splice variant, PSM-D, is elevated in prostate cancer metastases.