PURPOSE - We determined whether chronic administration of IFN-alpha at optimal biological dose inhibits angiogenesis of human pancreatic carcinoma growing in the pancreas of nude mice.
EXPERIMENTAL DESIGN - Cells of the human pancreatic cancer cell line L3.6pl were implanted into the pancreas of nude mice. Seven days later, groups of mice received s.c. injection with IFN-alpha alone (50,000 units biweekly or 10,000 units daily), i.p. injection with gemcitabine alone (125 mg/kg biweekly), or injection with both daily IFN-alpha and biweekly gemcitabine for 35 days. In a survival study, the mice were treated until they became moribund.
RESULTS - Biweekly treatments with 50,000 units of IFN-alpha alone were ineffective. In contrast, daily injections of IFN-alpha (10,000 units/day) alone, biweekly injections of gemcitabine alone, or the combination of IFN-alpha and gemcitabine reduced tumor volume by 53%, 70%, and 87%, respectively. Immunohistochemical analysis revealed that treatment with IFN-alpha alone or with IFN-alpha plus gemcitabine inhibited expression of the proangiogenic molecules basic fibroblast growth factor and matrix metalloproteinase 9 more than did treatment with gemcitabine alone. These treatments also decreased the staining of proliferating cell nuclear antigen within the tumor and induced apoptosis in tumor-associated mouse endothelial cells (staining with CD31/terminal deoxynucleotidyl transferase-mediated nick end labeling), leading to a decrease in microvessel density.
CONCLUSIONS - These data show that administration of IFN-alpha at optimal biological dose and schedule in combination with gemcitabine induced apoptosis in tumor-associated endothelial cells and decreased growth of human pancreatic cancer cells in the pancreas, leading to a significant increase in survival.