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Antitumor Effects of Polyribonucleotides for Mouse Transitional Cell Carcinoma Enhanced by Cyclophosphamide¹

Departments of Human Oncology [E. C. B., Y. A. S., D. S. G., G. T. B.] and Medicine [E. C. B.], Wisconsin Clinical Cancer Center, University of Wisconsin, Madison, Wisconsin 53792

Mouse bladder tumor (MBT-2), derived from a carcinogen-induced transitional cell carcinoma of the bladder, has proven a useful model for study of pathogenesis and prediction of cytotoxic drug sensitivity of human bladder carcinoma. To define optimal conditions for activity of the potent interferon inducer polyriboinosinic-polyribocytidylic acid [poly(I)·poly(C)] in this model, studies of dose, timing, and combinations with a cytotoxic drug were initiated. Poly(I)·poly(C) inhibited MBT-2 growth when 10⁵ or 10⁶ tumor cells were implanted. Tumor growth reduction was relatively more pronounced in mice inoculated with higher numbers of MBT-2 cells (10⁶) than in mice inoculated with an intermediate dose (10⁵) or small dose (10⁴). In mice inoculated with 10⁵ MBT-2 tumor cells, poly(I)·poly(C) (2.5 or 10 mg/kg i.p.) on Days 5 to 19 every other day reduced tumor size markedly. It had no effect, however, on tumor incidence or the time of their first detection. Treatment for a shorter period (alternate days from Days 11 to 19) resulted in less inhibition of tumor growth. Once treatment was discontinued, tumors grew progressively. Polyriboadenylic:polyribouridylic acid [poly(A)·poly(U)] (10 mg/kg) which inhibited tumor growth but to a lesser degree than poly(I)·poly(C) induced lower, less sustained levels of serum interferon. Cyclophosphamide, injected i.p. on Day 1, resulted in inhibition of tumor incidence and growth in direct proportion to the dose administered (25 to 200 mg/kg), but it was curative only at 30% lethal doses. When combined with poly(I)·poly(C) (2.5 or 10 mg/kg), cyclophosphamide (50 mg/kg) had an additive antitumor effect. Optimal inhibition of MBT-2 tumor growth occurred by combining cyclophosphamide (100 mg/kg) with poly(I)·poly(C) (2.5 mg/kg); eight of 14 mice were tumor free on Day 60.

¹ Supported in part by USPHS Research Grants CA 14520 and CA 27436 from the National Cancer Institute, the latter grant being obtained through the National Biadder Cancer Project. A partial, preliminary report of this work was presented (17).

² To whom requests for reprints should be addressed, at Department of Human Oncology, Wisconsin Clinical Cancer Center, K4/414, CSC, 600 Highland Avenue, Madison, WI 53792.

Received 3/30/84. Accepted 10/ 9/84.