Augmented antitumor effect of recombinant human interleukin-1 alpha by indomethacin

In murine syngeneic tumor models, the antitumor effect of recombinant human interleukin-1 alpha (rHu IL-1 alpha) was significantly augmented by oral coadministration of indomethacin (IND). The augmentation was more or less observed by various routes of rHu IL-1 alpha (i.m., i.v., and intratumoral routes), against various tumors (Meth A sarcoma, colon 26 adenocarcinoma, B16 melanoma, and Lewis lung carcinoma) and irrespective of administration timings (in early and late stages of tumor growth). This results suggests that prostaglandin E2 produced by host cells in response to rHu IL-1 alpha and/or by tumor mass might interfere with the antitumor activity of rHu IL-1 alpha and also that cyclooxygenase inhibitors such as IND might counteract such interference. In the combination of rHu IL-1 alpha with IND, its efficacious doses (5-50 micrograms/kg) against murine tumors were at least 300-3000 times lower than its median lethal dose (more than 15 mg/kg). In addition, IND partially prevented the loss of body weight attributed to rHu IL-1 alpha injections at relatively high doses. Combined use of rHu IL-1 alpha with IND seems to be desirable from both therapeutic and toxicological viewpoints.