Administration of optimal biological dose and schedule of interferon α combined with gemcitabine induces apoptosis in tumor-associated endothelial cells and reduces growth of human pancreatic carcinoma implanted orthotopically in nude mice

Purpose: We determined whether chronic administration of IFN-α 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-α 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-α 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-α alone were ineffective. In contrast, daily injections of IFN-α (10,000 units/day) alone, biweekly injections of gemcitabine alone, or the combination of IFN-α and gemcitabine reduced tumor volume by 53%, 70%, and 87%, respectively. Immunohistochemical analysis revealed that treatment with IFN-α alone or with IFN-α 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-α 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.