[en] X irradiation (5000 rads) was found to enhance the aryl hydrocarbon hydroxylase (AHH)activity of three cell lines. Radiation followed by induction with benz(a)anthracene (5 to 15 micron g/ml) produced a synergistic effect on AHH. These effects were highly significant and were observed most dramatically with a hamster tumor cell line, A(T₁)Cl-3, and to a lesser extent in secondary hamster embryo cells and mouse C3H/10T 1/2 CL8 cells

[en] Purpose: The retinoblastoma protein (pRB) is a key regulator of the G1 cell cycle checkpoint. Altered pRB expression has been documented in a significant percentage of muscle-invasive bladder cancers and has been associated with poorer overall survival. Since the relationship between pRB expression and radiation response is unknown, this was examined in patients treated between 1960 and 1983 with preoperative radiotherapy (50 Gy in 25 fractions) followed 4-6 weeks later by radical cystectomy. Materials and Methods: Immunohistochemical staining of pRB in paraffin-embedded tumor sections using WL-1 polyclonal anti-RB antibody was considered adequate in 98 of 100 pretreatment tumor samples. The overexpression of p53 by immunohistochemical staining using monoclonal antibody DO1 (n=97) and the apoptotic index (n=89) using morphologic criteria from hematoxylin and eosin stained slides were also quantified. In contrast to pRB, wherein a lack of pRB staining indicates altered expression, the presence of p53 staining is indicative of a putative p53 mutation. There were 46 patients in Stage T2, 28 in Stage T3a, and 24 in Stage T3b. The median age was 62 years and follow-up for those living was 85 months. Results: Staining for pRB was negative in 30% of the cases. Correlations were observed between pRB negativity and high pretreatment apoptosis level (p=0.06), more advanced clinical stage (p=0.01), increased clinical-to-pathologic downstaging (p=0.014), and more pathologic complete responses (Path-CRs; p=0.019). Several other factors were tested and none were associated with downstaging, including p53 expression or apoptotic index. Thus, RB status was the only pretreatment prognostic factor in the univariate analyses that correlated with downstaging. RB status was also independently related to Path-CR using multivariate logistic regression. Despite these significant relationships, no correlations between pRB staining and patient outcome were observed when the entire cohort was analyzed. Restriction of the analyses to Stage T3b patients, however, revealed that pRB negativity predicted for enhanced distant metastasis freedom (p=0.006, logrank) and overall survival (p=0.02). The only other significant predictors of distant metastasis for Stage T3b patients were p53 staining (p=0.02) and Path-CR (p=0.03), and for overall survival were p53 staining (p=0.003) and hemoglobin level (p=0.03). These data indicate that different mechanisms were responsible for the correlations of p53 and pRB status to distant metastasis and overall survival rates, since only pRB expression correlated with radiation response. To examine this further, the patients were divided into 4 groups based on p53 and pRB staining patterns. When this was done for the entire cohort, as well as for Stage T3b patients, superior distant metastasis freedom and overall survival rates were seen when there was no staining for either p53 or pRB. Hence altered pRB expression and wild-type p53 expression was associated with the best outcome, presumably because these attributes were complimentary. Conclusion: These data demonstrate that RB status measured by immunohistochemical staining is a strong correlate of radiation response, far beyond that of any other known prognostic factor. Because the loss of pRB function has been associated with a worse prognosis in other studies wherein radiotherapy was not used, it appears that this abnormality imparted enhanced radiosensitivity which counterbalanced the other related adverse characteristics. Moreover, the segregation of radiation response and patient outcome characteristics by the p53 and pRB immunohistochemical staining patterns suggests that these markers represent independent functional defects. pRB immunohistochemical staining status may be a useful marker for selecting patients for bladder preservation

[en] Cell culture studies have been performed to compare the mutagenic potential and the induction of sister chromatid exchanges for hematoporphyrin derivative photoradiation, ionizing radiation, and UV radiation. The mutation frequency in Chinese hamster ovary cells at the hypoxanthine-guanine phosphoribosyltransferase locus was measured using resistance to 6-thioguanine. Phenotypic expression time prior to mutation selection was also examined. Treatment with either X-rays or UV was effective in producing mutants resistant to 6-thioguanine, but treatment with hematoporphyrin derivative photoradiation (at comparable toxicity levels) did not induce any mutagenic activity above background levels. The hematoporphyrin derivative incubation and photosensitization conditions used in this study did induce sister chromatid exchanges at frequencies comparable to those induced by X-rays but at lower frequencies than for UV treatments