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Channing L. Hinman 419-530-1940 Phone |
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Institutions/Degrees
| B.S., 1972 | Brigham Young University |
| Ph.D., 1977 | University of California at Los Angeles (UCLA) |
| NRSA Fellowship, 1980-82 | Wayne State University |
Medicinal/pharmaceutical chemistry; biochemistry. Development and site-directed action of immunotoxic proteins and peptides of venom origin; animal model studies of the immunologic course and suppression of autoimmune diseases affecting the nervous system (e.g., experimental immune myasthenia gravis).
Research Interests
Members of the cardiotoxin/cytotoxin family of polypeptides derived from the venom of cobras differentially exhibit membrane effects upon cells such as cardiac myocytes, T-lymphocytes, and certain types of cancer cells. In the case of heart cells, depolarization rapidly follows toxin binding; at comparable toxin concentrations, susceptible cancer cells are lysed. Inhibition of cancer cell division without lysis occurs at submicromolar toxin concentrations. We have established that the region of the toxin that binds a target cell is distinct from the region that participates in its lytic activity, although the identity of the active site remains to be determined. We are investigating this question by examining the relative activities of synthetic peptides derived from these toxins. We shall also apply molecular biological techniques to define the lytic region and to learn the extent to which effects on tumor cells can be selectively enhanced relative to their effects on heart cells. With regard to the mechanism of action of these toxins, we are investigating their membrane binding sites using photoaffinity probes to covalently couple toxin derivatives. Other studies using fluorescent probes should allow us to learn whether toxin molecules aggregate at the cell surface prior to effecting lysis, and additional studies should indicate the depth of membrane penetration by these toxin derivatives.
Although membrane-disruptive cytotoxins might be applied in the eventual treatment of selected cancers, autoimmune diseases, or AIDS, because of their intrinsic affinity for heart cells, substantial modifications in their structure might be required in order to reduce potential deleterious effects. One of these modifications could replace the native binding region of a toxin with an antibody component to achieve specific target cell delivery. We have constructed immunoconjugates containing membrane-active toxins. Selectivity for human T-lymphocytes over mouse T-cells has been demonstrated. Further development of such immunoconjugates should provide agents which: 1) could be used as an adjunct to reduce the dose of other chemotherapeutic agents; 2) could be used directly to achieve cytostasis or cytotoxicity; 3) could be used to enhance inhibition of drug resistance due to the glycoprotein pump in targeted cells, which has already been shown to be reversed by cytotoxin application in vitro.
Representative Publications
