Nitric oxide (NO) is a potent short-lived and short range bioactive molecule, which plays a key role in physiological and
pathological processes including
inflammation and
cancer. Detrimental effects of excessive NO production during
septic shock have been well recognized. We tested the hypothesis that '
capillary leak syndrome' following systemic
interleukin-2 (IL-2)
therapy resulted from a cascade of events leading to the induction of NO which, directly or indirectly, injured capillaries and caused fluid leakage. Our results provided the first direct evidence that the induction of active
NO synthase (NOS) leading to the overproduction of NO is instrumental in IL-2-induced capillary leakage in mice and that successful blocking of this overproduction with chronic
oral administration of NOS inhibitors can mitigate this leakage without interfering with the beneficial antitumor effects of
IL-2 therapy. NO blocking agents can, in fact, improve IL-2-induced antitumor effector cell activation, as well as
tumor regression. In our studies, NO blocking agents alone reduced the growth and
metastasis of a murine mammary
carcinoma, at least in part, by mitigating the invasion and angiogenesis-stimulating role of
tumor-derived NO. Thus, NOS inhibitors may be useful in treating certain
tumors and serve as valuable adjuncts to systemic
IL-2 based
immunotherapy of
cancer and
infectious diseases.