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Antitumor Effects of Recombinant Humant Interleukin 1 in RIF-1 and Panc02 Solid Tumors¹

Laboratories of Experimental Therapeutics [P. G. B., N. K., V. O.] and Cell Biology [C. S. J., P. F.], AMC Cancer Research Center, Denver, Colorado 80214

The antitumor effects of recombinant human interleukin 1 (IL-1) were determined in RIF-1 and Panc02 murine solid tumors. Acute tumor hemorrhage was observed in both models as early as 3 h after a single 25 µg/kg IL-1 treatment and was quantitated by the intratumor accumulation of ⁵⁹Fe-labeled erythrocytes (RBC). The IL-1-mediated hemorrhagic response was maximal 6–12 h after treatment and greater in Panc02 tumors than in RIF-1 tumors. Hemorrhagic responses to RIF-1 tumors growing in athymic nude mice were similar to those seen for RIF-1 tumors in C3H/HeJ mice.

This acute vascular injury was accompanied by progressive edema in tumors but not in skin or muscle. In RIF-1 tumors, the extracell water volume at 12 h after IL-1 (395 µl/g) was nearly twice that in untreated controls (215 µl/g). IL-1 also produced marked reductions in tumor blood flow as early as 1 h after treatment. Maximal blood flow restriction was seen at 6 h after IL-1. Although restricted blood flow was observed in tumors for up to 48 h, IL-1 effects on muscle, liver, and skin blood flow were transient with recovery by 12 h after treatment.

IL-1 (up to 0.4 ng/ml for 72 h) was not toxic to RIF-1 tissue culture cells in vitro, but 0.2 ng/ml IL-1, for 20 h, reduced the clonogencity of RIF-1 cells in primary explant cultures by approximately 50%. In vivo, the clonogenic cellularity of RIF-1 tumors was reduced by 70%, 24 h after a single 25 µg/kg treatment. Increased clonogenic cell proliferation was observed at 24 h, and rapid repopulation of the clonogenic cell population was seen by 48 h. Although IL-1 transiently slowed the growth of RIF-1 tumors, no significant regrowth delay was observed. In Panc02 tumors, cell proliferation was also inhibited after IL-1. Recovery, however, was delayed and occurred more slowly than in RIF-1 tumors. Significant growth inhibition and regrowth delay (5 days) was observed in Panc02 tumors after a single IL-1 treatment.

The results of these studies show that IL-1 has significant effects on the pathophysiology of both RIF-1 and Panc02 tumors in vivo. Further, our results indicate that these effects may be mediated through the activation of a non T-cell, adherent cell population residing in the tumor at the time of IL-1 treatment.

¹ This work was supported by Grants CA33188 and CA33939 from Department of Health, Education, and Welfare (to P. F.) and a gift to the AMC Cancer Research Center from Stephen L. Wenner.

² To whom requests for reprints should be addressed, at Laboratory of Experimental Therapeutics, AMC Cancer Research Center, 1600 Pierce Street, Denver, CO 80214.

Received 5/16/88. Revised 8/ 1/88. Accepted 8/ 4/88.

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