Larry K KeeferLaboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick, MD, USA F1000 Faculty Member (since 04 July 2001)
The Chemistry Section is studying the chemistry and biology of the multifaceted bioregulatory agent, nitric oxide (NO), with two principal goals in mind: 1) finding ways to target NO to specific sites in the body for important research and drug development applications; 2) characterizing the possible role of NO as a determinant of cancer risk. In our drug development effort, considerable progress has resulted from our discovery that many diazeniumdiolates (compounds containing the [N(O)NO]- functional group) spontaneously release NO in physiological fluids. Half-lives of examples characterized thus far range from 2 seconds to 3 weeks. In animal experiments, these compounds compare favorably as radiosensitizers of hypoxic tumors, anticoagulants, vasodilators, cytostatic agents, antimicrobials, and inducers of penile erection to agents presently in use clinically for these purposes. Current work is aimed at localizing NO delivery to specific tissues for possible therapeutic applications. Approaches under development include: attachment of the [N(O)NO] group to proteins that interact cell-specifically with the target tissue; design of prodrugs metabolized to NO by enzymes found only in the target cell type; and incorporation into insoluble solids that can be placed into physical contact with the site to be dosed with NO.
Regarding the possible role of NO in carcinogenesis, we are characterizing the surprising differences in mutational spectra observed on exposure to NO under different conditions, as well as attempting to establish mechanisms by which NO either increases or diminishes cancer risk. Of particular interest in the latter connection are disorders in which an infection or inflammatory episode both greatly upregulates endogenous NO synthesis and predisposes to tumorigenesis; in such cases, modulation of the NO flux (e.g., with selective inhibitors of NO synthase) could provide insight into the carcinogenic versus anticarcinogenic potential of this important bioeffector species.
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