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Interleukin 15 Protects against Toxicity and Potentiates Antitumor Activity of 5-Fluorouracil Alone and in Combination with Leucovorin in Rats Bearing Colorectal Cancer¹

Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263 [S. C., Y. M. R.], and Immunex Corporation, Seattle, Washington 98101 [A. B. T.]

5-Fluorouracil (FUra) modulated by leucovorin (LV) is active in the treatment of colorectal cancer. Diarrhea and stomatitis are the most common dose-limiting toxicities. We have developed a model system in rats bearing a transplantable colon carcinoma sensitive to FUra therapy with dose-limiting toxicity profiles similar to what is observed in patients treated with either daily or weekly schedules of FUra plus LV. Interleukin 15 (IL-15), a cytokine that shares many biological activities with IL-2, was used at different doses (25, 100, and 400 µg/kg) and schedules (three doses before a single dose of FUra, FUra/LV daily x 5, or before each week of FUra/LV weekly x 4, or three doses before a single dose of FUra or FUra/LV daily x 5, then twice daily x 5 for a total of 11 doses) to evaluate its role in the modulation of the therapeutic selectivity of FUra alone and modulated by LV. IL-15 induced a dramatic decrease in chemotherapy-induced gastrointestinal toxicities, significant potentiation of antitumor activity, and an increased therapeutic index of FUra administered on single dose, daily x 5 and weekly x 4 schedules. In contrast, IL-2 (400 µg/kg) significantly potentiated the toxicity of FUra administered as a single i.v. push, with minimal potentiation of the antitumor activity.

Taken together, the results clearly demonstrated the ability of IL-15, but not IL-2, to provide significant improvement of the therapeutic index of FUra alone and in combination with LV. The clinical relevance of the results obtained in this model system needs to be confirmed.

¹ Supported in part by Grant DHP147 from the American Cancer Society and Immunex Corporation.

² To whom requests for reprints should be addressed, at Roswell Park Cancer Institute. Elm and Carlton Streets, Buffalo, NY 14263. Phone: (716) 845-3394; Fax: (716) 845-8857; E-mail: scao@sc3101.med.buffalo.edu.

Received 11/ 7/97. Accepted 2/18/98.

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