Differential effects of human natural interferon-alpha and mismatched double-stranded RNA against a human renal cell carcinoma xenograft.
The antitumor effects of natural human IFN-alpha and mismatched dsRNA against the human renal cell carcinoma cell line 786-0 were studied both in a clonogenic soft agar assay and in the nude mouse. The 786-0 cells were sensitive in vitro to the antiproliferative effects of IFN-alpha in a dose-response manner, up to 3000 IRU/ml. These cells were also sensitive, in a dose-dependent manner, to mismatched dsRNA in the clonogenic assay. Mismatched dsRNA was effective in inhibiting tumor growth (p less than 0.001) in nude mouse xenografts, with regression of the tumor mass seen in all animals. A significant increase in survival (p less than 0.001) was seen in the mismatched dsRNA treated group. In contrast, IFN-alpha did not inhibit tumor growth in vivo, even though significant titers of IFN-alpha (greater than 3,000 IRU/ml) were found in the serum shortly after treatment. Mismatched dsRNA did not induce the production of human IFNs by the tumor cells in vitro. Assays of mouse IFN induction and their in vitro antigrowth effects indicated that the in vivo antiproliferative effect of mismatched dsRNA was probably not due to potentiation of any direct effects by the induced mouse IFNs. Tumor growth inhibition appeared to occur, at least in part, from the significant augmentation (p less than 0.01) of natural killer cell activity by mismatched dsRNA, as measured in the spleen cells of treated mice. These results suggest that, although both IFN-alpha and mismatched dsRNA can be directly antiproliferative against this tumor, either the IFN-independent antitumor effects of mismatched dsRNA or the mismatched dsRNA-induced augmentation of the host immune response plays a major role in tumor regression. Potentially, both mechanisms may be important in this system.
Hubbell
H R
HR
Department of Neoplastic Diseases, Hahnemann University, Philadelphia, Pennsylvania 19102.
Pequignot
E C
EC
Shanabrook
K R
KR
Carter
W A
WA
Williams
R D
RD
Strayer
D R
DR
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000628:therapy*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007370:Interferon Type I / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012330:RNA, Double-Stranded / Q000494:pharmacology / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects; D014410:Tumor Stem Cell Assay
D007370:Interferon Type I; D012330:RNA, Double-Stranded