Role of nitric oxide in IL-2 therapy-induced capillary leak syndrome

Amila Orucevic, Peeyush K. Lala

Research output: Contribution to journalReview article

25 Citations (Scopus)

Abstract

Nitric oxide (NO) is a potent short-lived and short range bioactive molecule, which plays a key role in physological 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 overproduciton 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 murein 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.

Original languageEnglish (US)
Pages (from-to)127-142
Number of pages16
JournalCancer and Metastasis Reviews
Volume17
Issue number1
DOIs
StatePublished - Jan 1 1998

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Capillary Leak Syndrome
Interleukin-2
Nitric Oxide
Nitric Oxide Synthase
Neoplasms
Therapeutics
Peptidoglycan
Pathologic Processes
Septic Shock
Immunotherapy
Communicable Diseases
Oral Administration
Breast Neoplasms
Neoplasm Metastasis
Inflammation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Role of nitric oxide in IL-2 therapy-induced capillary leak syndrome. / Orucevic, Amila; Lala, Peeyush K.

In: Cancer and Metastasis Reviews, Vol. 17, No. 1, 01.01.1998, p. 127-142.

Research output: Contribution to journalReview article

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N2 - Nitric oxide (NO) is a potent short-lived and short range bioactive molecule, which plays a key role in physological 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 overproduciton 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 murein 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.

AB - Nitric oxide (NO) is a potent short-lived and short range bioactive molecule, which plays a key role in physological 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 overproduciton 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 murein 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.

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