Combined 5-Fluorouracil/Systemic Interferon-β Gene Therapy Results in Long-Term Survival in Mice with Established Colorectal Liver Metastases

• Published in: Clinical cancer research 2004-02, Vol.10 (4), p.1535-1544
• Main Authors: CHOI, Eugene A, HANQIN LEI, MARON, David J, MICK, Rosemarie, BARSOUM, James, YU, Qian-Chun, FRAKER, Douglas L, WILSON, James M, SPITZ, Francis R
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Animals; Antimetabolites, Antineoplastic - pharmacology; Antineoplastic agents; Apoptosis; Biological and medical sciences; Cell Line, Tumor; Colorectal Neoplasms - mortality; Colorectal Neoplasms - pathology; Colorectal Neoplasms - therapy; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fluorouracil - pharmacology; Genetic Therapy; Humans; In Situ Nick-End Labeling; Inflammation; Interferon-beta - blood; Interferon-beta - genetics; Interferon-beta - metabolism; Liver - metabolism; Liver Neoplasms - mortality; Liver Neoplasms - secondary; Liver Neoplasms - therapy; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Pharmacology. Drug treatments; Time Factors; Treatment Outcome; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-0040-03

Preclinical in vitro and in vivo studies have demonstrated synergistic interactions between 5-fluorouracil (5-FU) and type I and II IFNs against human colorectal cancer cells. Despite these activities, randomized human trials have failed to identify a clinical benefit for this combination treatment. These limited clinical results may be secondary to the short half-life of recombinant IFN protein and the increased systemic toxicities of 5-FU/IFN combinations. We have previously reported an adenoviral-mediated IFN-β gene therapy strategy, which may circumvent the pitfalls of recombinant IFN therapy. However, a dose-dependent toxicity and acute inflammatory response to systemically administered adenovirus vectors may limit the clinical application of this therapy. The combination of adenoviral-mediated IFN-β gene therapy and 5-FU resulted in tumor regression, apoptosis, and improved survival in an established liver metastases model. These therapeutic effects were observed at a significantly lower vector dose than we had previously reported and with limited toxicity. This approach may allow for an effective clinical application of this therapy and warrants additional investigation.