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Wolfram Samlowski

Professor of Medicine and of Pathology

B.A. Ohio State University

M.D. Ohio State University

Research

References

 

Wolf Samlowski's Lab Page

Research

Interleukin-2 (IL-2) is capable of activating cytolytic lymphocytes that have a remarkable capacity to kill virtually all cancer cells.   When IL-2 is administered to patients with kidney cancer or melanoma, however, only a low frequency (5-10%) of complete tumor regressions is observed.   My basic science immunology laboratory is evaluating mechanisms of how IL-2 induces anticancer effects in vivo in order to understand this apparent paradox, as well as to try to develop techniques for increasing the clinical activity of IL-2.    We have helped develop and are testing novel biodegradable polymer delivery systems for sustained IL-2 release in tumor sites.   In addition, we have developed a novel gene therapy approach using a IL-2 gene engineered with a transmembrane domain (IL-2tm) designed to transfect tumor cells and co-stimulate host lymphocytes that can recognize tumor antigens.   Preclinical development of these agents is actively proceeding in the laboratory.    

IL-2 also induces severe and dose limiting side effects.   These include hypotension (severely low blood pressure), vascular leak syndrome (marked fluid retention, non cardiac pulmonary edema, decreased kidney function) and neuropsychiatric toxicity (confusion, hallucinations, agitation).   We have developed experimental models to better understand the pathophysiologic mechanisms underlying these toxicities and to develop pharmacologic inhibitors.   Our studies have shown that oxidative radicals, such as superoxide and peroxynitrite mediate hypotension by causing catecholamine oxidation, preventing constriction of blood vessels to counteract low blood pressure. Vascular leak appears to be mediated by nitric oxide.   We have just recently developed murine models to study brain toxicity due to IL-2.   A number of pharmacologic inhibitors have been developed in my laboratory, and are in various stages of preclinical and clinical testing.   It should be noted that many of these toxicities are induced by other cytokines (IL-1, TNF, IFN g , VEGF).   Thus these studies are likely to have broad clinical relevance.

 

Catecholamine oxidation by oxygen radicals and peroxynitrite: Based on studies of IL-2 induced hypotension, we have proposed the following schema for oxidation of catecholamines by superoxide   or peroxynitrite, resulting in formation inactive "adrenochrome" compounds that cannot constrict blood vessels.   Superoxide-induced catecholamine oxidation is believed to be autocatalytic.   Potential adrenochrome effects are also indicated.

References