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

Solorzano CC, Hwang R, Baker CH, Bucana CD, Pisters PW, Evans DB, Killion JJ, Fidler IJ
Clin Cancer Res. 2003 9 (5): 1858-67

PMID: 12738744

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.

MeSH Terms (23)

Animals Antineoplastic Combined Chemotherapy Protocols Apoptosis Cell Division Deoxycytidine Dose-Response Relationship, Drug Endothelium, Vascular Fibroblast Growth Factor 2 Humans Implants, Experimental Interferon-alpha Interleukin-8 Male Matrix Metalloproteinase 9 Mice Mice, Nude Neoplasms, Experimental Neoplasm Transplantation Pancreatic Neoplasms Platelet Endothelial Cell Adhesion Molecule-1 Survival Rate Tumor Cells, Cultured Vascular Endothelial Growth Factor A

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