Synergistic therapy of human ovarian carcinoma implanted orthotopically in nude mice by optimal biological dose of pegylated interferon alpha combined with paclitaxel.
The purpose of this study was to optimize the antitumor andantiangiogenic activities of pegylated IFN-alpha (PEG-IFN-alpha)alone or in combination with paclitaxel against SKOV3ip1 human ovarian cancer cells growing orthotopically in female nude mice. Seven days after the i.p. implantation of tumor cells, groups of mice (n = 10) were injected s.c. once per week (for 4 weeks) with different doses of PEG-IFN-alpha (3,500, 7,000, 35,000, and 350,000 units). PEG-IFN-alpha at 7,000 units significantly decreased tumor incidence and volume. At doses exceeding 7,000 units, PEG-IFN-alpha was less efficacious. In another set of studies conducted 7 days after the i.p. implantation of SKOV3ip1 cells, groups of mice (n = 10) received (once per week for 4 weeks) either s.c. administrations of PEG-IFN-alpha (7,000 units), i.p. injections of paclitaxel (100 microg/wk), or a combination of PEG-IFN-alpha and paclitaxel. The mice were killed 7 days after the last treatment, and tumor burden was assessed. Administration of PEG-IFN-alpha at the optimal biological dose (7,000 units) in combination with paclitaxel significantly decreased angiogenesis and progressive growth of human ovarian carcinoma cells in a synergistic fashion. The combination therapy produced the most significant inhibition in expression of the proangiogenic molecules basic fibroblast growth factor and matrix metalloproteinase-9. Decreased microvessel density, decreased proliferating cell nuclear antigen staining, and increased endothelial cell apoptosis also correlated with therapeutic success. Collectively, the data suggest that combining the optimal biological dose of PEG-IFN-alpha with paclitaxel may provide a novel and effective approach to the treatment of human ovarian carcinoma.
Tedjarati
Sean
S
Departments of Cancer Biology and Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Baker
Cheryl H
CH
Apte
Sachin
S
Huang
Suyun
S
Wolf
Judith K
JK
Killion
Jerald J
JJ
Fidler
Isaiah J
IJ
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015152:Blotting, Northern; D002455:Cell Division / Q000187:drug effects; D004357:Drug Synergism; D016228:Endothelial Growth Factors / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage; D016209:Interleukin-8 / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011092:Polyethylene Glycols; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D016209:Interleukin-8; D008222:Lymphokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018809:Proliferating Cell Nuclear Antigen; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D011092:Polyethylene Glycols; D020780:Matrix Metalloproteinase 9; C417083:peginterferon alfa-2b; D017239:Paclitaxel; C100416:peginterferon alfa-2a