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Antiproliferative and Immunomodulatory Actions of ß-Interferon and Double-Stranded RNA, Individually and in Combination, on Human Bladder Tumor Xenografts in Nude Mice¹

The Barry Ashbee Leukemia Research Laboratories, Department of Hematology/Oncology, Hahnemann University, Philadelphia, Pennsylvania 19102

A cell line, RT4, derived from a human transitional cell carcinoma of the bladder, was grown as a xenograft in athymic mice. The growth of the xenografts was inhibited by ß-interferon (IFN-ß), polyriboinosinic acid·polyribocytidilic acid, the mismatched double-stranded RNA analogue r(I)_n·r(C₁₂,U)_n, and to a lesser extent recombinant IFN-ß, when treatment was initiated at the time of tumor inoculation. In contrast, the growth rate of established tumors, approximately 6 mm in diameter at the initiation of therapy, was inhibited by both double-stranded RNAs, but not natural IFN-ß, indicating a possible tumor size dependence on the effectiveness of IFN-ß. Combinations of natural or recombinant IFN-ß with either polyriboinosinic acid·polyribocytidilic acid or r(I)_n·r(C₁₂,U)_n gave an antagonistic effect regardless of tumor mass at the initiation of treatment. This antagonism could be overcome by alternating r(I)_n·r(C₁₂,U)_n and natural IFN-ß treatment. Natural killer cell activity against RT4 cells in culture was augmented in the spleens of mice treated with r(I)_n·r(C₁₂,U)_n, but not in those treated with natural IFN-ß. RT4 cells treated in culture with IFN-ß, however, were significantly less efficient as targets for natural killer cells from r(I)_n·r(C₁₂,U)_n-treated and control spleens. These results indicate that: (a) the effectiveness of IFN-ß may be related to the tumor mass; (b) double-stranded RNAs appear to work, at least partially, in an indirect, immunomodulatory manner; (c) combination therapy can yield an antagonistic rather than an additive or synergistic antitumor effect; and (d) strategic scheduling can overcome the antagonistic effect of combination therapy.

¹ This work was supported by USPHS Grant P01 CA-29545 from the National Cancer Institute.

² To whom requests for reprints should be addressed.

Received 8/ 1/84. Revised 2/14/85. Accepted 2/27/85.

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