Basic and Clinical Investigation for Modulation of Radiation Sensitivity in Radiation Therapy combined by Genetherapy

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Correlations between radiation response and various biological parameters including oncogenes, apoptosis relating gene expressions of tumors and hypoxia relating proteins were investigated for prediction of radiation sensitivity predominantly relating local control probability following radiation therapy.Immunohistochemical study and various DNA/RNA analysis for human specimens were performed for obtaining parameters relating to radiation sensitivity as well as analysis for tumor cell lines and experimental animals as materials. Prognosis was analyzed by various parameters including c-erbB-2 oncoprotein expression (CerbB-OE), p21, p27, p53 protein expression, Platelet-derived endothelial cell growth factor (PD-ECGF), inducible NOS (iNOS) and Hypoxia-inducible factor-1α (HIF-1α).RESULTS. Cancer cells that were positive for PD-ECGF showed intranuclear and cytoplasmic staining patterns. Of the 71 patients, 31 were negative for PD-ECGF and 40 were positive. The 5-year survival rate of the … More PD-ECGF-positive patients was significantly better than that of the PD-ECGF-negative patients (p=0.026). Cancer cells that were positive for iNOS showed a cytoplasmic staining pattern. Forty one patients were negative for iNOS and 27 were positive. No significant prognostic correlation existed between iNOS-negative and iNOS-positive patients.c-erbB-2/HER2 positive staining was observed in cancer membrane and cytoplasm. Nine specimens were positive for c-erb-B2/HER2 and the total positive rate was 43%. The 5-year survival rate was 38% for all patients. The 5-year survival rate of the c-erbB-2/HER2 positive patients was 28%, representing a trend toward poorer prognosis than the 52% of negative patients (p=0.10). Multivariate analysis using Cox proportional hazards model showed that c-erbB-2/HER2 was an independent prognostic factor (p=0.024).Cancer cells, and degenerated or swollen cancer cells caused by radiotherapy that were positive for p21, p27, and p53 showed an intranuclear reactivity. The mean p27-labeling index before radiotherapy was significantly decreased at 27Gy, conversely, the mean p53-labeling index was significantly increased at 27Gy. The high p27-labeling index before radiotherapy was significantly associated with good disease free and metastasis free survivals. The high p53-labeling index before radiotherapy was a poor overall survival. All the 2 samples before radiotherapy showed no mutations of p53 (exons 5-8), that implied the wild type. Four out of 5 samples at 27Gy showed mutations of p53 (exons 5 and 7), and the remaining one had no mutations.Of 38 patients, high expression of HIF-1α, p53, bax, and bcl-2 were seen in 17 (45%), 22 (58%), 15 (39%), and 15 (39%) patients, respectively, and 28 patients (74%) showed the positive infection with HPV. There was a significant positive correlation between high HIF-1α expression and disease recurrence (p<0.05). Furthermore, HIF-1α had a significant correlation with the recurrence free survival rate (p=0.04). No statistical significance was noted between high HIF-1α expression and local control rate (p=0.17), whereas HIF-1α status predicted distant metastasis with strong significance (p=0.03). Conversely, other factors demonstrated no impact on clinical outcome of patients with stage IIIB cervical carcinoma.CONCLUSIONS. PD-ECGF-positivity in cancer cells is regarded as a predictive factor for good prognosis in cervical squamous cell carcinoma treated with radiotherapy alone. c-erbB-2/HER2 expression of cervical tumors might be a predictive parameter of the prognosis after radiation therapy for PALNM of advanced uterine cervical carcinoma patients. The high p27 and low p53 expression in cancer cells before radiotherapy is a predictive good factor for the prognosis of patients with cervical squamous cell carcinoma treated with radiotherapy alone. The p27 and p53 indexes showed reversal patterns of changes in periods from before radiotherapy to at 27Gy, implying one of the radiotherapeutic effects. The phenomenon of the p53 oncogene changing the wild type of p53 before radiotherapy into the mutant type at 27Gy may be the radiation effect. HIF-1α is an important prognostic factor, especially for predicting future metastasis after radiation therapy for patients with Stage IIIB squamous cell carcinoma of the cervix. Less