Repair of sublethal radiation damage by capillaries.

Neovascularization was induced surgically in normally avascular canine corneas to study the repair of sublethal damage in slowly proliferating capillary endothelial cells. Neovascularization was stimulated for 7 days after split dose treatments with ⁶Co γ-rays. Corneal tissue samples were evaluated by quantitative morphometric methods. A time recovery curve was drawn by plotting per cent capillary volume vs time between two equal doses. A typical “Elkind type” of time recovery response was observed. A split dose response assay resulted in an incremental dose D₂—D₁ of 265 rad at the 1% capillary volume level. The results suggest a substantial repair capacity for capillary endothelial cells.     

In vitro chemoresistance and biomarker profiles are unique for histologic subtypes of epithelial ovarian cancer

OBJECTIVES: To determine whether there is a relationship between histologic subtype of epithelial ovarian cancer and chemoresistance, we evaluated ovarian carcinomas of six histologic subtypes and correlated histology with in vitro drug response. Biomarker profiles (p53, Her-2 neu, and EGFR) were also evaluated to determine if their expression patterns were associated with histology. METHODS: In vitro drug response profiles for different histologic subsets of epithelial ovarian carcinomas exposed to standard relevant chemotherapy agents were determined in the Extreme Drug Resistance assay (EDR). Immunohistochemistry techniques were employed to determine biomarker expression. RESULTS: Of 5195 referred serial cases of epithelial ovarian cancer, there were 2660 papillary serous, 303 endometrioid, 142 mucinous, 102 clear cell, 952 undifferentiated carcinomas, and 42 tumors of low malignant potential. For the samples as a whole, the incidences of extreme drug resistance to the tested chemotherapeutic agents were cisplatin 10%, carboplatin 16%, cyclophosphamide 16%, doxorubicin 40%, gemcitabine 21%, paclitaxel 22%, and topotecan 13%. When compared to papillary serous tumors, mucinous tumors were more frequently resistant to cisplatin (10% vs. 18%) but less frequently resistant to topotecan (13% vs. 5%) and doxorubicin (42% vs. 16%). Endometrioid tumors were less resistant to cisplatin (10% vs. 6%) and doxorubicin (42% vs. 20%). Clear cell and undifferentiated tumors had the lowest rates of EDR to paclitaxel (13% and 18%) and cyclophosphamide (7% and 11%), while borderline tumors showed high rates of EDR to these agents (52% and 63%, respectively). With respect to biomarker profiles, mP53 was detected in 46%, Her-2 neu in 16%, and EGFR in 30% of the cases evaluated. As compared to all other subtypes, clear cell carcinomas had significantly higher Her-2 neu expression (19%). Relative to papillary serous carcinomas, borderline tumors exhibited significantly lower rates of mP53 expression (60% vs.17%). CONCLUSIONS: We found significant differences in the frequencies of extreme drug resistance to chemotherapeutic agents and biomarker expression among histologic subtypes of epithelial ovarian cancer. The data collected in this investigation may provide a guide for stratification of patients entering clinical trials based on histology and biomarker expression.     

Increased levels of urokinase plasminogen activator receptor in prostate cancer cells derived from repeated metastasis

To understand alterations to the urokinase system that may occur in progressively metastatic prostate cancer cells, we assessed urokinase plasminogen activator receptor (uPAR) expression, in vitro motility towards vitronectin, urokinase plasminogen activator (uPA)-induced growth and growth factor regulation of uPAR expression in three cell lines—PC-3 and two derivatives from secondary metastases, PC-3M and PC-3MM2. DU-145 and Tsu-Pr1 cells were included for comparative purposes. uPAR expression increases with metastatic passage in these cell lines and accompanies increased growth and motility responses in the presence of uPA. Growth factors TGF1 and IGF-1 induce uPAR in all three prostate cancer lines; however, PC-3M and PC-3MM2 cells also respond to bFGF. Of the cell lines tested, PC-3MM2 most uniformly respond to added TGF1, IGF-1 and bFGF. These results show that in two progressive derivatives from repeated metastasis of PC-3 cells, constitutive and growth factor-induced uPAR expression is enhanced. This increased uPAR facilitates the properties of growth and motility.