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W R Fair

Publications and source records attributed to W R Fair.

At least 19 recordsLinked to original sources
PubMed2000

Intravesical liposome-mediated interleukin-2 gene therapy in orthotopic murine bladder cancer model.

Using a novel orthotopic MBT-2 murine bladder tumor model, we evaluated the feasibility of intravesical gene therapy utilizing a cationic liposome, DMRIE/DOPE. Superficial bladder tumors were consistently established by intravesical instillation of 5x10(5) MBT-2 cells in syngeneic C3H female mice. In situ gene transfer to bladder tumors was accomplished via intravesical instillation of plasmid DNA/DMRIE/DOPE lipoplex. Beta-Galactosidase (beta-gal) gene expression was preferentially evident in bladder tumors and was present for at least 7 days after a single 30 min in situ transfection. Murine interleukin-2 (IL-2) gene was used for treatment of 3-day-old pre-established bladder tumors. Forty percent of animals treated with IL-2 gene were completely free of tumors by 60 days following the initial tumor implantation, while all control groups treated with beta-gal gene died. Those animals initially cured of pre-established tumors were completely resistant to a subsequent tumor re-challenge and their splenocyte-derived cytotoxic T lymphocytes were shown to be specific to MBT-2 cells, indicating that immunological memory against MBT-2 tumors was elicited by the treatment. These results demonstrate the possibility of an effective clinical application of this in situ intravesical IL-2 gene delivery system to high-risk superficial bladder tumors, obviating a need for tumor procurement and ex vivo gene transfer.

Administration, Intravesical↗
PubMed2000

Historical perspective on prostate brachytherapy.

Brachytherapy--radiation delivered close to or within a tumor--had its origins at the beginning of this century. Its use in prostate cancer was delayed first by the view that this was a relatively radioresistant cancer and then by clinical experience showing high failure and morbidity rates. More recently, technological innovations such as ultrasonography and computer-based treatment planning have made prostate brachytherapy a reasonable treatment option for many patients.

Brachytherapy↗
PubMed2000

Radical cystectomy for invasive bladder cancer: contemporary results and remaining controversies.

The impact of stage progression of superficial cancer to invasive disease is profound. However, the optimal-timed management of invasive bladder cancer is still controversial. Pelvic lymph node dissection and radical cystectomy are considered to be the optimal therapy regarding local tumor control and ultimate cure of cancer, whereas chemotherapy offers the only viable but limited option for patients with distant metastasis or locally advanced disease. Identification of conventional and molecular prognostic factors to predict cancer-specific survival following radical cystectomy is one important step to identify candidates that may benefit from early cystectomy or adjunct chemotherapy. With this background, the results of historic and contemporary radical cystectomy series for carcinoma of the bladder are reviewed.

Cystectomy↗
PubMed2000

Expression of c-kit and kit-ligand in benign and malignant prostatic tissues.

The tyrosine kinase receptor c-kit and its ligand [kit ligand (KL) or stem cell factor (SCF)] exert a broad range of biological activities during organogenesis and normal cell development. Recent studies have revealed that altered c-kit levels occur in a variety of malignancies and cancer cell lines. KL has also been shown to stimulate the growth of malignant cells, as well as to promote chemotaxis. We had previously reported expression of KL in stroma cells of normal human prostate. The present study was undertaken in order to analyze the patterns of expression of c-kit and KL in a well characterized set of prostatic tissues, including normal prostate (n=4), benign prostatic hyperplasia (BPH) (n=53) and adenocarcinoma (n=46) samples. The distribution of c-kit and KL proteins was studied by immunohistochemical analyses, while transcript levels were determined by in situ hybridization with specific RNA probes on a subset of the benign and malignant tissues referred above. In addition, reverse-transcriptase polymerase chain reaction (RT-PCR) was performed to determine levels of c-kit and KL expression in cultures of epithelial and stroma cells, as well as in the prostate cancer cell lines LNCaP, DU145 and PC3. c-kit protein in normal prostate was exclusively detected in mast cells by immunohistochemistry and in situ hybridization. However, c-kit transcripts, but not c-kit protein, were detected in low levels and with an heterogeneous pattern in basal epithelial cells of ducts and acini. c-kit in BPH was detected in epithelial cells in 9 of 53 (17%) specimens. c-kit protein expression in malignant epithelial cells was identified in 1 of 46 (2%) tumors. However, c-kit transcripts were detected in low levels by in situ hybridization in most of the tumors analyzed. KL protein and transcripts in normal prostate were detected in high levels in stroma cells. However, epithelial cells were unreactive for anti-KL antibody, but showed low levels of KL transcripts mainly in cells of the basal layer. Basal epithelial cells in hyperplastic glands showed KL expression in 13 of 53 (24%) specimens. KL protein in tumor cells was noted in 18 of 46 (39%) cases. c-kit transcripts were not found in normal prostate and in the 3 cancer cell lines analyzed by RT-PCR, however, it was present in cultured epithelial cells of BPH, and in cultures of stroma cells from both normal and BPH. The majority of cultured cell lines of epithelial and stromal origin displayed considerable levels of KL. In addition all prostate cell lines studied showed significant levels of KL transcripts. In summary, co-expression of c-kit and KL in a subset of BPH cases may suggest an autocrine mode of signaling. Data from this study reveals that altered patterns of c-kit and KL expression are associated with BPH and adenocarcinoma of prostate. It appears that KL induces mast cells proliferation and maturation and enhances their release of protease. This could explain the accumulation of mast cells at tumor sites, a phenomenon that was not observed in normal prostate or BPH samples.

Adenocarcinoma↗
PubMed2000

Bryostatin 1 induces prolonged activation of extracellular regulated protein kinases in and apoptosis of LNCaP human prostate cancer cells overexpressing protein kinase calpha.

Previously, we reported that 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced apoptosis of LNCaP human prostate cancer cells was accompanied by prolonged translocation of protein kinase C (PKC)alpha to non-nuclear membranes and that TPA-resistant LNCaP cells had down-regulated PKCalpha. Here we show that 10 nM bryostatin 1 induced transient membrane translocation and down-regulation of PKCalpha, prolonged translocation of PKCdelta and epsilon to non-nuclear membranes, and did not induce cell death but blocked TPA-induced apoptosis. To test the hypothesis that inhibition of TPA-induced apoptosis by bryostatin 1 was due to down-regulation of PKCalpha, we inducibly overexpressed PKCalpha in LNCaP cells. Overexpression of PKCalpha alone did not induce apoptosis, even in clones that contained much more membrane-bound, active PKCalpha than was observed in TPA-treated untransfected LNCaP cells. However, the addition of 10 nM bryostatin 1 to PKCalpha-overexpressing LNCaP cells did not yield down-regulation of PKCalpha and induced extensive apoptosis. Immunoblot analysis revealed that TPA induced prolonged hyperphosphorylation of Raf-1 and activation of extracellular-regulated/mitogen-activated protein kinases 1 and 2 in untransfected LNCaP cells, as did bryostatin 1 in PKCalpha-overexpressing cells. On the other hand, bryostatin 1 induced only transient hyperphosphorylation of Raf-1 and activation of extracellular-regulated/mitogen-activated protein kinases 1 and 2 in untransfected LNCaP cells. These results confirm a role of prolonged membrane-associated PKCalpha in PKC activator-mediated LNCaP apoptosis and suggest involvement of the mitogen-activated protein kinase pathway.

Antineoplastic Agents↗
PubMed2000

Effectiveness of combined interleukin 2 and B7.1 vaccination strategy is dependent on the sequence and order: a liposome-mediated gene therapy treatment for bladder cancer.

We have developed a novel liposome-mediated immunogene therapy using interleukin 2 (IL-2) and B7.1 in a murine bladder cancer model. A carcinogen-induced murine bladder cancer cell line, MBT-2, was transfected with cationic liposome 1,2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide/dioleolylphosphatidylethanolamine and IL-2 plasmid. The optimized transfection condition generated IL-2 levels of 245-305 ng/10(6) cells/24 h, 100-fold higher than the levels seen with retrovirus transfection. Ninety percent of the peak level of IL-2 production was maintained for up to 11 days after transfection. Animal studies were conducted in C3H/HeJ female mice with 2 x 10(4) MBT-2 cells implanted orthotopically on day 0. Multiple vaccination schedules were performed with i.p. injection of 5 x 10(6) IL-2 and/or B7.1 gene-modified cell preparations. The greatest impact on survival was observed with the day 5, 10, and 15 regimen. Control animals receiving retrovirally gene-modified MBT-2/IL-2 cell preparations had a median survival of 29 days. Animals receiving the IL-2 liposomally gene-modified cell preparation alone had a median survival of 46 days. Seventy-five percent of animals receiving IL-2 followed by B7.1 gene-modified tumor vaccines were the only group to show complete tumor-free survival at day 60. All of these surviving animals rejected the parental MBT-2 tumor rechallenge and survived at day 120 with a high CTL response. In conclusion, liposome-mediated transfection demonstrates a clear advantage as compared with the retroviral system in the MBT-2 model. Multi-agent as opposed to single-agent cytokine gene-modified tumor vaccines were beneficial. These "targeted" sequential vaccinations using IL-2 followed by B7.1 gene-modified tumor cells significantly increased a systemic immune response that translated into increased survival.

Animals↗
PubMed2000

Three-dimensional ultrasound analyses of the prostate.

Although conventional ultrasonography has proven to be clinically useful for depicting many types of cancerous lesions, it cannot distinguish reliably between cancerous and noncancerous tissue of the prostate. Therefore, conventional transrectal ultrasonography (TRUS) is used primarily for general evaluations of the gland and for guiding biopsies based on clearly imaged anatomic features such as the capsule, seminal vesicles, and urethra. Spectrum analysis extracts ultrasound signal parameters associated with biopsy-proven tissue types, and these parameters are then classified using neural network tools such as learning vector quantization, radial basis, and multilayer perceptron algorithms. Classification of cancerous and noncancerous prostate tissue using neural networks produces receiver operating characteristic (ROC) curves of 0.87 +/- 0.04 compared with 0.64 +/- 0.04 for conventional ultrasonography. To image the prostate using these methods, parameter values are computed at each pixel location, then translated into a score for the likelihood of cancer using a look-up table generated using the best classification algorithm. The score for cancer likelihood is expressed as a gray-scale or color value, and the resulting image may be useful to guide biopsies or therapy. Changes in parameter or score values over time potentially can be used to assess progression of disease or efficacy of therapy.

Adenocarcinoma↗
PubMed2000

Update on Memorial Sloan-Kettering Cancer Center studies of neoadjuvant hormonal therapy for prostate cancer.

PURPOSE: We report the results of surgery in 520 patients with clinically localized carcinoma of the prostate (CaP) who received preoperative neoadjuvant hormonal therapy (NHT) for 3 to 11(+) months. METHODS: The results in the NHT patients were compared with those in 1,413 men having surgery without NHT at our institution during the same time period. In the group without pretreatment, the median and mean follow-up was 36 and 21 months, respectively. In the patients receiving NHT, the median follow-up was 33 months and the mean 41 months. RESULTS: The overall disease-free survival (DFS) rate (serum prostate specific antigen [PSA] concentration < or = 0.2 ng/mL) was 75% at 5 years and 50% at 10 years. There was no statistically significant difference in overall DFS rate between men who had NHT and those who did not. No DFS advantage could be demonstrated for those patients with a presenting PSA >20 ng/mL who received NHT compared with patients with the same PSA concentration who did not receive NHT. Despite our previous experience indicating improved survival with NHT in men with a presenting PSA of > 10 ng/mL, we could find no advantage to NHT in enhancing DFS. At a median survival of 35 months (mean 41 months) in 201 men with an initial PSA > or = 10 ng/mL, 70% had an undetectable PSA concentration at 5 years compared with 72% at the same time point in men presenting with PSA <10 ng/mL. In the group expected to have the best surgical result; i.e. those men whose preoperative PSA was < or = 7 ng/mL, there was no DFS difference in men given NHT compared with those having no hormonal manipulation. Patients presenting with stage T(1) disease had a significantly better DFS than those with either T(2) or T(3) CaP. However, within each stage, the addition of NHT to surgery did not result in a higher DFS rate. The 5- and 10-year DFS rates for stage T(1) were 80% and 64%, for T2 disease 78% and 50%, and for T3 disease 67% and 50%. There was a statistically significant difference (P < or = 0.003) in survival between stage T(1) and stage T(2) disease, but no significant difference in DFS was noted in patients presenting with stage T(2) compared with T3 cancer (P = 0.431). Gleason score was not a significant predictor of durable DFS, and the addition of NHT did not improve the DFS within groups of patients with similar Gleason scores. Men with only one or two positive biopsy cores did significantly better than those with more than three positive cores (P = 0.06). There was a significant difference in DFS between men who had organ-confined disease and those with disease outside the gland (P = 0.0003). However, NHT did not improve DFS. The presence of positive surgical margins was a negative prognostic factor (P = 0. 001). Men who received NHT had a statistically lower positive margin rate (P = 0.001), but NHT did not increase the likelihood of a durable DFS (P = 0.175). The duration of NHT did not affect the DFS (P = 0.100 for <3 v >3 months). CONCLUSION: There appears to be no subset of men undergoing radical prostatectomy in whom the routine administration of NHT is beneficial despite the statistically significant improvement in the pathologic findings.

Adenocarcinoma↗
PubMed1999

Clinical significance of small (less than 0.2 cm3) hypoechoic lesions in men with normal digital rectal examinations and prostate-specific antigen levels less than 10 ng/mL.

OBJECTIVES: Most men diagnosed with prostate cancer in 1998 presented with a normal digital rectal examination (DRE) and minimal elevations in serum prostate-specific antigen (PSA) (less than 10 ng/mL). Considerable attention is often given toward identifying small hypoechoic (less than 0.2 cm3) lesions at the time of transrectal ultrasound-guided prostate biopsy. We sought to determine the significance of these lesions and whether an additional biopsy of this area is clinically useful. METHODS: A prospective data base containing detailed information on 614 biopsies performed by a single urologist was examined. All patients with a hypoechoic lesion underwent sextant prostate biopsy plus a separately labeled core directed through the hypoechoic area. Eighty-one patients who fit the following criteria were assessed: PSA less than 10 ng/mL, normal DRE, and hypoechoic lesion volume less than 0.2 cm3. RESULTS: The mean age of this group was 63.5 years, and the mean PSA was 7.1 ng/mL. Of the 81 patients with small hypoechoic lesions, 20 (24.7%) were positive for cancer in at least one prostatic core. Of the 81 hypoechoic area biopsies (HABs), 14 (17.3%) were positive for cancer; 1 (1.2%) demonstrated high-grade prostatic intraepithelial neoplasia, and 66 (81 .5%) were negative. In 11 of the patients (78.6%) with positive HABs, at least one additional core was positive for cancer. In 3 of the patients (21.4%) with positive HABs, no additional cores were positive for cancer (P<0.05). CONCLUSIONS: A significant proportion of small hypoechoic lesions in patients with early T1c prostate cancer are positive for malignancy. Although the overall yield of separate hypoechoic area biopsy is low (3.7%), approximately 15% of cancers would be missed if directed HABs were not performed (P<0.05). Identification and biopsy of small hypoechoic lesions are indicated in this group of patients.

Adult↗
PubMed1999

Effect of neoadjuvant hormonal therapy on prostatic intraepithelial neoplasia and its prognostic significance.

PURPOSE: We studied the effect of neoadjuvant hormonal therapy on prostatic intraepithelial neoplasia in patients undergoing radical prostatectomy and assessed the effect of prostatic intraepithelial neoplasia on disease recurrence as measured by serum prostate specific antigen (PSA). MATERIALS AND METHODS: A total of 278 patients with clinically localized prostate cancer were included in phase II and III studies evaluating radical prostatectomy alone versus radical prostatectomy following neoadjuvant hormonal therapy at Memorial Sloan-Kettering Cancer Center between October 1991 and August 1996. Patient data related to prostatic intraepithelial neoplasia were analyzed. RESULTS: Of 275 evaluable patients 145 (52.7%) had prostatic intraepithelial neoplasia. Of 50 patients treated with neoadjuvant hormonal therapy (hormone group) 22 (44%) had a lower incidence of prostatic intraepithelial neoplasia compared to 69 of 80 controls (86.3%) (chi-square test p<0.0001). Of 262 patients (95.3%) with followup PSA 44 (16.8%) had PSA recurrence at a median followup of 32 months, with a median time to recurrence of 30 months. PSA recurrence was noted in 23 of 145 patients with compared to 21 of 130 without prostatic intraepithelial neoplasia (chi-square test p = 0.95), and did not significantly differ between the hormone group (25 of 142, 17.6%) and controls (19 of 130, 14.6%) (chi-square test p = 0.45). CONCLUSIONS: While patients treated with neoadjuvant hormonal therapy had significantly lower incidence of prostatic intraepithelial neoplasia, neither prostatic intraepithelial neoplasia nor neoadjuvant hormonal therapy significantly affected PSA recurrence at a median followup of 32 months.

Antineoplastic Agents, Hormonal↗
PubMed1999

Prostate specific antigen doubling time after radical prostatectomy: effect of neoadjuvant androgen deprivation therapy.

PURPOSE: We determined the predictors of prostate specific antigen (PSA) doubling time in patients with relapse after radical prostatectomy as well as whether PSA doubling time is shorter in those treated versus not treated with neoadjuvant androgen deprivation therapy. MATERIALS AND METHODS: We calculated PSA doubling time in 204 patients with PSA relapse after radical prostatectomy who were or were not treated with neoadjuvant androgen deprivation therapy. Analysis of covariance was used to determine the effect of clinical and pathological parameters on PSA doubling time, and the proportion of variability explained by these parameters. RESULTS: Clinical stage, and combined clinical stage and margin status, clinical stage and androgen deprivation therapy status, androgen deprivation therapy status and time to PSA relapse, and androgen deprivation therapy status and pretreatment PSA were significant predictors of PSA doubling time. Any variable or combination of variables explained up to only 21% of PSA doubling time variability. When stratified by pretreatment PSA, clinical stage and biopsy grade, the difference in doubling times in patients treated with or without neoadjuvant androgen deprivation therapy was significant only for 4.1 to 10 ng./ml. PSA. In this group mean doubling time plus or minus standard deviation in patients receiving neoadjuvant androgen deprivation therapy and those treated only with radical prostatectomy was 7.6+/-1.0 and 15.4+/-2.6 months, respectively. CONCLUSIONS: Our study indicates that it is difficult to predict PSA doubling time in an individual. The small proportion of variability in PSA doubling time explained by the interaction of androgen deprivation therapy status and other variables indicates that these factors are not clinically significant.

Androgen Antagonists↗
PubMed1999

The impact of primary stage on survival in patients with lymph node positive bladder cancer.

PURPOSE: Contemporary series indicate that survival of cystectomy candidates with node positive bladder cancer is favorable when the primary tumor is confined to the bladder wall and lymph node involvement is minimal. However, these series lack node negative controls with a similar tumor stage to determine accurately the true impact of pelvic lymphadenectomy and radical cystectomy on survival. MATERIALS AND METHODS: We retrospectively analyzed disease specific survival in 686 consecutive cystectomy candidates of whom 193 (28.1%) had node positive disease at radical cystectomy. To correct for bias towards higher P category in the node positive group we subdivided groups into organ and nonorgan confined categories to compare outcome between node negative and node positive cases. RESULTS: The frequency of organ confined disease in node positive cases was 22.8% compared to 59.2% in node negative cases. Although when analyzing the entire group disease specific survival was significantly decreased in node positive cases, after correction for P stage we found no statistically significant differences in survival between N0 and N1 cases in the organ confined group (p = 0.4267). Differences between N0 and N1 cases in nonorgan confined disease were statistically significant (p = 0.0276). Significance levels were more pronounced when cases with N2 or N3 categories were compared with node negative cases. Comparison of survival between node negative and N2 or N3 in either group revealed significant differences indicating limited impact of surgery alone at this disease stage. CONCLUSIONS: Patients with N1 disease seem to benefit from pelvic lymphadenectomy and radical cystectomy as evidenced by similar outcome in those with node negative disease and similar P stage of the primary tumor. However, the observed benefit rapidly disappears when more than 1 lymph node is involved and additional therapy other than surgery seems appropriate.

Adult↗
PubMed1999

Vitamin E inhibits the high-fat diet promoted growth of established human prostate LNCaP tumors in nude mice.

PURPOSE: Prostate cancer has become an important public health problem in the Western world. It is currently the most common diagnosed cancer and the second leading cause of cancer deaths among North American men. Prostate cancer possesses a unique descriptive epidemiology which suggests that environmental factors (such as dietary fat consumption) play a pivotal role in tumor progression. Data from our institution have demonstrated that diets high in fat content can accelerate the growth of human LNCaP prostate cancer cells. One of the hypothesized mechanisms of dietary fat induced growth is oxidative stress. Our purpose was to determine the effect of supplemental Vitamin E, a potent intracellular antioxidant, on the high-fat promoted growth of transplanted LNCaP cells in the athymic mouse. MATERIALS AND METHODS: Tumors were induced by subcutaneous injection of 10(6) LNCaP cells. Mice were fed a control diet consisting of 40.5% of total calories from dietary fat. Once tumors were formed, PSA values were obtained and animals were randomized into 4 groups of 12. The animals were then assigned to one of 4 dietary plans. Group 1 received the control diet of 40.5%-kcal fat. Group 2 received the 40.5%-kcal fat diet plus supplemental Vitamin E. Group 3 received a diet of 21.2%-kcal fat. Group 4 received the 21.2%-kcal fat diet plus supplemental Vitamin E. Food intake, animal weights, and tumor volumes were recorded weekly. Survival analyses with time to a target volume of 0.523 cm.3 (defined as failure) were used to compare tumor growth among the 4 groups. Two-sided tests (log rank test) with alpha set at 0.05 were used to determine significance. RESULTS: Tumor growth rates were highest in the animals fed a 40.5%-kcal fat diet (p <0.05 group 1). Tumors in animals fed 40.5%-kcal fat plus Vitamin E, 21.2%-kcal fat, and 21.2%-kcal fat plus Vitamin E, experienced statistically indistinguishable growth rates. No significant differences were noted in total ingested calories, animal weight gain or initial PSA levels. CONCLUSIONS: These data suggest that the mechanism of dietary fat induced growth of human prostate cancer cells is mediated by oxidative stress. It also raises the possibility of a therapeutic benefit of vitamin E in preventing prostate cancer.

Animals↗
PubMed1999

The role of dietary manipulation in biochemical recurrence of prostate cancer after radical prostatectomy.

In 1999, we continue to be faced with difficulties in treating prostate cancer, which remains the leading cause of cancer and the second leading cause of cancer-related deaths in men. In the prostate-specific antigen (PSA) era, we must also determine which therapies, if any, are appropriate for the treatment of a biochemical or PSA relapse. In view of the limited number of efficacious and durable treatments for prostate cancer recurrence, the medical community has had to investigate nontraditional therapies. In the recent past, an expanding body of evidence has implicated certain nutrients in carcinogenesis and cancer progression. This article discusses the role of diet in prostate carcinogenesis and the rationale for dietary manipulation as a treatment strategy for the prevention of primary and secondary (recurrent) prostate cancer.

Diet↗
PubMed1999

Pelvic lymph node dissection can be curative in patients with node positive bladder cancer.

PURPOSE: We analyze outcome in a large cohort of patients with bladder cancer metastatic to the regional lymph nodes using disease specific survival as the end point. MATERIALS AND METHODS: To identify predictors for outcome a large series of 193 consecutive patients with regional lymph node metastases operated on from 1980 to 1990 at Memorial Sloan-Kettering Cancer Center was retrospectively analyzed. RESULTS: Among various clinical and pathological parameters, univariate and multivariate analyses identified only P (p = 0.0001) and N categories (p = 0.0006) as parameters predicting disease specific survival. In patients who received chemotherapy or irradiation either as part of a nonrandomized clinical protocol or on an ad hoc basis no beneficial impact on disease specific survival could be demonstrated. Survival was also not affected by pathological grade and other histological parameters, since pathological features in patients with node positive bladder cancer are uniformly shifted towards high grade lesions with vascular or lymphatic invasion and a solid appearance on histological analysis. CONCLUSIONS: Nodal metastases carry a poor prognosis despite pelvic lymphadenectomy and radical cystectomy. Nevertheless, some node positive cases with otherwise localized bladder cancer and/or low N category appear to benefit from surgery. Our findings of improved outcome in some individuals with node positive disease should be considered in the design of clinical trials evaluating the effects of adjuvant or neoadjuvant treatment strategies, and emphasize the importance of randomized studies to assess the results of these approaches.

Actuarial Analysis↗
PubMed1998

Mapping, genomic organization and promoter analysis of the human prostate-specific membrane antigen gene.

Prostate-specific membrane antigen (PSMA) is a 100 kDa type II transmembrane protein with folate hydrolase and NAALAdase activity. PSMA is highly expressed in prostate cancer and the vasculature of most solid tumors, and is currently the target of a number of diagnostic and therapeutic strategies. PSMA is also expressed in the brain, and is involved in conversion of the major neurotransmitter NAAG (N-acetyl-aspartyl glutamate) to NAA and free glutamate, the levels of which are disrupted in several neurological disorders including multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease and schizophrenia. To facilitate analysis of the role of PSMA in carcinoma we have determined the structural organization of the gene. The gene consists of 19 exons spanning approximately 60 kb of genomic DNA. A 1244 nt portion of the 5' region of the PSMA gene was able to drive the firefly luciferase reporter gene in prostate but not breast-derived cell lines. We have mapped the gene encoding PSMA to 11p11-p12, however a gene homologous, but not identical, to PSMA exists on chromosome 11q14. Analysis of sequence differences between non-coding regions of the two genes suggests duplication and divergence occurred 22 million years ago.

Antigens, Surface↗