Prostate-specific antigen density: a new prognostic indicator for prostate cancer.

PURPOSE: Prostate specific antigen density, previously described as a ratio of serum prostate specific antigen to the volume of the prostate, has been shown to be an important factor in the discrimination of patients with occult metastatic disease and patients with benign versus malignant prostatic disease. We undertook a retrospective study to determine if prostate specific antigen density was a predictor of outcome following definitive conformal radiation therapy. METHODS AND MATERIALS: Between January 1989 and August 1991, 86 patients with localized prostate cancer (confined to the prostate, periprostatic tissue, or seminal vesicles) were treated in the Department of Radiation Oncology, Columbia-Presbyterian Medical Center with definitive radiation therapy using computed tomography-guided conformal technique. Thirteen patients were excluded on the basis of prior prostatectomy, hormonal therapy, or no pretreatment prostate specific antigen measurement. Seventy-three patients were evaluable: 19% (14/73) American Urologic Association Stage A (T1), 41% (30/73) B (T2), and 40% (29/73) C (T3). Prostate specific antigen density was defined as the ratio of the pretreatment serum prostate specific antigen to the prostate volume as determined from computed tomography treatment planning scans. Pretreatment prostate specific antigen density was calculated for each patient and ranged from 0.04-3.85 with a mean and median value of 0.66 and 0.33, respectively. Prostate specific antigen failure was defined as a rise above normal level or, for patients whose nadir was above 4 ng/ml, an increase of greater than 10% above nadir. Mean prostate specific antigen follow-up was 13 months (range 2.3-31 months) by which time 66% of patients had normal prostate specific antigen (< or = 4 ng/ml) levels. RESULTS: Nine patients experienced prostate specific antigen failure. The mean prostate specific antigen density of patients with disease-free survival versus failures was 0.53 and 1.6, respectively (p < 0.05). Kaplan-Meier analysis showed that patients with a prostate specific antigen density < or = 0.3 (n = 30) had 100% actuarial disease-free survival at 30 months compared with 62% for patients with prostate specific antigen density > 0.3 (n = 43, p < 0.01). Patients with a prostate specific antigen density < or = 0.6 (n = 52) and > 0.6 (n = 21) had an 88% and 57% actuarial disease-free survival at > 24 months (p < 0.05). CONCLUSION: Prostate specific antigen density was an excellent predictor of disease-free survival (p < 0.01) and was superior to clinical stage (p > 0.05), Gleason's score (p > 0.05), and pretreatment prostate specific antigen (p < 0.05). These results suggest that patients with low prostate specific antigen density (< or = 0.3), including those with locally advanced clinical stage, high Gleason's score, or elevated pretreatment prostate specific antigen, do well with conventional radiation therapy and should not be subjected to high risk protocols. Further follow-up will be required to determine if patients with low prostate specific antigen density will have improved overall survival.

Transcription at bacteriophage T4 variant late promoters. An application of a newly devised promoter-mapping method involving RNA chain retraction.

Bacteriophage T4 late promoters display a conserved sequence that extends over about 18 base pairs, in which the central 8-base pair sequence (TATAAATA in the nontranscribed strand) is absolutely conserved. Transcription by T4-modified RNA polymerase in vitro nevertheless initiates within a cluster of 6 overlapping variant T4 late promoters that deviate from the absolutely conserved sequence at one or two positions. One of these variant promoters is dominant, and its sequence implies that two of the absolutely conserved nucleotides (underlined above) are not essential. Three other variant promoters that contain only one of the deviations found in the dominant variant promoter are, at best, utilized weakly, suggesting that sequences outside the absolutely conserved segment are important for promoter function. A newly devised method, based on arrest of RNA chain elongation with ribonucleotide analogs and its reversal, has been used to precisely map initiation within the overlapping promoter cluster. Multiple cycles of RNA chain arrest, pyrophosphorolysis, and resynthesis can be executed. This process permits a precise stepwise control of the advance of a transcription complex through a gene.

Correlations between transcription of a yeast tRNA gene and transcription factor-DNA interactions.

A partly purified fraction from Saccharomyces cerevisiae has a RNA polymerase III transcription factor activity and contains protein which binds specifically to two internal promoter regions of RNA polymerase III-transcribed genes. The influence of ionic strength and of dimethyl sulfoxide on specific binding to a S. cerevisiae tRNAleu3 gene has been analyzed by DNase I protection (footprinting) and by nitrocellulose filter binding. The effects of these agents on binding correlate with their effects on transcription and on the stability of transcription complexes. Dimethyl sulfoxide stabilizes binding and transcription complexes against dissociation by NaCl, with 10% dimethyl sulfoxide compensating for the addition of 50-60 mM NaCl. Binding of protein in the 5' proximal part of the S. cerevisiae tRNAleu3 gene is more NaCl-sensitive than binding in the 3' proximal part.