An adenovirus (Adv) retaining normal E1A but lacking the 55 kDa E1B protein replicates preferentially in TP53-deficient cancer cells including pancreatic cancer cell lines, resulting in the oncolysis ...of the tumor. When tumor cells are exposed to hypoxia, hypoxia-inducible factor-1alpha (HIF-1alpha) is stabilized and activated to promote the transcription of several genes such as vascular endothelial growth factor (VEGF), but in the presence of E1A hypoxia-induced VEGF m-RNA synthesis is inhibited by E1A binding to p300. In this study, we demonstrated that the cancer cells infected with a mutant Adv in which the p300 binding site in E1A was partially deleted induced a higher expression level of VEGF as compared to those of Adv with normal E1A. An immunoprecipitation study for E1A confirmed that mutant E1A had a reduced binding capacity for p300. Although the expressions of HIF-1alpha m-RNA were almost the same in both cancer cells infected with the mutant Adv and those with the wild Adv, the amount of HIF-1alpha protein in cancer cells infected with the wild E1A Adv was lower than in those infected with the mutant E1A type Adv. In vivo, in contrast to the angiogenesis treated with mutant E1A, wild-E1A inhibited tumor angiogenesis significantly. These results suggested that E1A suppressed the production of VEGF and inhibited tumor angiogenesis by binding with p300, resulting in the inhibition of the HIF-1alpha-mediated transcription of genes through binding to HRE. This study demonstrates, for the first time, the effect of an oncolytic replication-competent Adv in inhibiting tumor angiogenesis.
To clarify the significance of increased adenosine deaminase (ADA) isozyme activities in synovial fluid (SF) from patients with rheumatoid arthritis (RA).
ADA isozyme activities were measured using ...colorimetric assays. Concentrations of matrix metalloproteinase-9 (MMP-9) were measured by ELISA.
Levels of ADA isozyme activities in RA SF were significantly higher than those from patients with osteoarthritis and patients with traumatic injuries. Significant positive correlations between MMP-9 concentration and ADA activities were observed in RA SF (MMP-9 vs total ADA: r = 0.880; vs ADA1: r = 0.829; vs ADA2: r = 0.823; p < 0.001).
Elevated levels of ADA activities were found in SF from patients with RA. There were significant positive correlations between MMP-9 and ADA isozymes. These results may reflect the inflammatory condition of patients with RA.
Objective
To assess the kinetics of prostate specific antigen (PSA) and the degree of PSA suppression, to better understand the efficacy and limitations of delayed/salvage radiation therapy after ...radical prostatectomy.
Patients and methods
The PSA doubling time was calculated in patients with biochemical failure after radical prostatectomy and in those who underwent delayed/salvage radiation therapy. Patients in whom PSA was undetectable by conventional assay after irradiation were followed using a hypersensitive PSA assay.
Results
Of 125 patients who underwent radical prostatectomy for clinically resectable prostate cancer, 47 developed biochemical failure at a mean of 11.8 months after surgery; 38 of these patients underwent radiotherapy (36 for isolated biochemical failure and two for local progression with elevated PSA levels). The mean (sd) PSA doubling time after surgery was 14.6 (16.2) months (n=44) and after radiation therapy it was 13.3 (23.9) months (n=32). Eleven of 30 evaluable patients (37%) had a sustained PSA suppression lasting at least 12 months after radiotherapy. Only the time to biochemical failure after surgery approached statistical significance for predicting a durable response to radiotherapy (P=0.08). The mean nadir value of PSA in the 11 patients with at least 12 months of sustained PSA suppression was 0.032 ng/mL at 26.9 months.
Conclusions
The rapidity with which PSA levels double after surgery may provide a clinically significant indication of the nature of these recurrent tumours, which deserve the best possible attempt at cure. Slow‐growing tumours with longer PSA doubling times may be better candidates for delayed/salvage radiation therapy. Larger studies involving more patients are needed to determine whether the PSA doubling time can define subgroups for which specific treatment strategies should be developed.
The optimal protocol for combining high dose rate brachytherapy and external beam irradiation as treatment for localized prostate cancer is unknown. Toxicity rates and clinical and biochemical ...outcomes should be evaluated to validate the current treatment protocol.
Fifty-eight patients were treated for prostate cancer with high dose rate brachytherapy followed by 30 Gy of external beam radiation therapy. Toxicity during treatment and for 12-18 months thereafter, and treatment-related morbidity, were evaluated. Physician-assessed treatment-related toxicity was graded at the time of occurrence using the Radiation Therapy Oncology Group morbidity criteria. Four separate self-administered questionnaires were used to collect longitudinally demographic data and general and prostate disease-related measures of quality of life.
Various degrees of rectal bleeding due to radiation proctitis were experienced by 13 patients (22%) at a median time of 11 months. Two of these patients needed hospitalization to undergo laser coagulation of the rectal mucosa. Study patients had statistically significant decreases in five SF-36 domains during the first month of treatment. All measures recovered by 12 months. Sexual function was not affected by irradiation. Lower urinary tract symptoms assessed by IPSS/QOL scores worsened significantly during the first month of treatment but later recovered to baseline levels. Physician-assessed RTOG scores failed to detect these changes.
Morbidity associated with combined radiation therapy was greatest during the first month of treatment and affected quality of life significantly. Most measures recovered to baseline levels by 12 months following radiation therapy. Although the current protocol appears acceptable, measures should be taken to decrease treatment-related morbidity further.
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