Therapeutic effect of recombinant human tumor necrosis factor in ovarian carcinoma xenograft in nude mice

Abstract

Tumor necrosis factor (TNF) has been found to have in vitro and in vivo cytotoxicity against a variety of mouse and human experimental tumors. Synergistic effect with interferon-γ (IFN) has also been reported. We examined the therapeutic effect of TNF and IFN using the human ovarian carcinoma cell line NIH:OVCAR-3 intraperitoneally transplanted in nude mice. Approximately 10 to 15 million cells were injected intraperitoneally in 80 nude mice. One week later the animals were divided into four treatment groups of 20 animals each: (1) untreated controls, (2) daily ip injections of 5 μg TNF, (3) daily ip injections of 5 × 10 4 U of IFN, and (4) daily ip injections of 5 μg TNF and 5 × 10 4 U of IFN. After 13 weeks of treatment, when 50% of the control animals were dead of disease, a survival analysis was performed. The remaining animals underwent laparotomies (comparable to second-look in humans) at Weeks 15, 18, 20, and 22 to determine the presence of tumor in various tissues by histologic examination. A statistically significant survival difference was found between the untreated control group and the groups that received TNF or TNF plus IFN ( P < 0.0001). The TNF effect was further reflected in decreased serum CA-125 levels compared with controls ( P < 0.001). Only one out of 20 animals receiving TNF or TNF in combination with IFN was found to have intraperitoneal tumor at the time of laparotomy, whereas all the untreated controls had gross intraabdominal carcinomatosis. These results, in addition to existing preclinical data, may form the basis for clinical protocols employing intraperitoneal TNF in selected ovarian carcinoma patients.