EFFECTS OF N-G-METHYL-L-ARGININE, AN INHIBITOR OF NITRIC-OXIDE SYNTHESIS, ON INTERLEUKIN-2-INDUCED CAPILLARY LEAKAGE AND ANTITUMOR RESPONSES IN HEALTHY AND TUMOR-BEARING MICE

We tested whether treatment with an inhibitor of nitric oxide synthesi s (Nc-methyl-L-arginine, MeArg) can ameliorate interleukin-2(IL-2)-the rapy-induced capillary leak syndrome in healthy or tumor-bearing mice without compromising the antitumor effects of IL-2 therapy. Healthy or C3-L5-mammary-adenocarcinoma-bearing C3H/HeJ mice were treated with o ne or two rounds of various doses of IL-2 (ten injections, i. p., ever y 8 h) or MeArg (ten injections s. c., every 8 h) or their combination . In an additional experiment, MeArg was given chronically in the drin king water, rather than s. c, to healthy mice subjected to one round o f therapy as above. Mice were killed 1 h after their last IL-2 injecti on to measure the water content of the lungs and pleural cavities (mar kers of capillary leakage), NO production (given by NO2- and NO3- leve ls in the serum and pleural effusion), as well as the effect of therap ies on the primary tumor size and number of spontaneous lung metastati c nodules. Results revealed that all doses of IL-2 (7500-35000 Cetus U /injection), as well as both rounds of IL-2 therapy, caused capillary leakage. However, no pleural effusion was seen after the second round in any of the IL-2-treated groups. MeArg therapy, given subcutaneously (5-20 mg kg(-1) injection(-1) in healthy and 20 mg kg(-1) injection(- 1) in tumor-bearing mice), did not ameliorate IL-2-induced capillary l eakage in either group of mice, and did not compromise antitumor effec ts of IL-2. However, subcutaneous MeArg therapy alone reduced the grow th of the primary tumors, the occurrence of spontaneous lung metastase s and the amount of tumor-induced pulmonary edema. When MeArg therapy was given orally (1 mg/ml drinking water), a substantial drop in NO pr oduction, as well as reduction in capillary leakage was noted in IL-2- treated healthy mice. These findings suggest that NO inhibitors could be a valuable adjunct to IL-2 therapy of cancer and infectious disease s.