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

• Published in: Clinical cancer research 2003-05, Vol.9 (5), p.1858-1867
• Main Authors: Solorzano, Carmen C, Hwang, Rosa, Baker, Cheryl H, Bucana, Corazon D, Pisters, Peter W, Evans, Douglas B, Killion, Jerald J, Fidler, Isaiah J
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis - drug effects; Cell Division - drug effects; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Dose-Response Relationship, Drug; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Fibroblast Growth Factor 2 - metabolism; Humans; Implants, Experimental; Interferon-alpha - administration & dosage; Interleukin-8 - metabolism; Male; Matrix Metalloproteinase 9 - metabolism; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism; Survival Rate; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 1078-0432; 1557-3265

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.