Interleukin 15 protects against toxicity and potentiates antitumor activity of 5-fluorouracil alone and in combination with leucovorin in rats bearing colorectal cancer
Cao, S.; Troutt, A.B.; Rustum, Y.M.
Cancer Research 58(8): 1695-1699
1998
ISSN/ISBN: 0008-5472 PMID: 9563485 Document Number: 487016
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 mug/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 daffy X 5 for a total of 11 doses) to evaluate its role in the modulation of the therapeutic selectivity of FUrs 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, dally X 5 and weekly X 4 schedules. In contrast, IL-2 (400 mug/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.