Richard W. Voellmy - US grants

Expression of heat shock protein (hsp) or stress protein genes is enhanced by a diverse set of chemicals and treatments that are stressful to cells. Frequently, pretreatment with an agent that induces hsp synthesis renders cells resistant to subsequent challenges with the same or other agents under conditions that would otherwise cause death. The genes are ubiquitous and encode a small number of relatively highly conserved proteins. Several hsps are known to bind to other proteins, some of them (including the 70,000 dalton or hsp70 proteins) having a preference for unfolded polypeptides, and to function as molecular chaperones, facilitating important cellular processes such as protein synthesis and trafficking. Regulation of transcription of hsp genes is mediated by hsp gene-specific transcription factor HSF whose activity appears to be regulated by the concentration of unengaged hsp70. Because of their regulation, hsps are being discussed as possible molecular- biological markers for toxicity. Based on their properties we hypothesize that hsps, especially those of the hsp70 class, may also be intricately related to the molecular mechanisms of action of many toxicants. This proposal is to characterize, using a mouse hepatotoxicity model, hsp gene expression in response to exposure of the organism to well-characterized toxicants, and to test the hypotheses that hsps protect hepatic cells from damage by many toxicants, that they may participate in the mechanisms of action of many toxicants by interacting, directly or indirectly, with adducted proteins produced by these toxicants following bioconversion, and that upregulation of hsp gene expression reflects the cell's response to toxicants, serving to provide extra hsps to "neutralize" adducted proteins.

DESCRIPTION (provided by applicant): Current chemotherapy of cancer typically employs combinations of powerful anti-neoplastic agents. Most therapeutic combinations include anti-neoplastic agents that cause loss of scalp hair (chemotherapy-induced alopecia). Particularly, frequently used alopecia-inducing anti-neoplastic agents are cyclophosphamide, adriamycin, etoposide, taxol and vincristine. Alopecia is clearly the most feared side effect of chemotherapy. Patients have been known to refuse chemotherapy treatment because of it, and it seems not unreasonable to suspect that the psychological devastation resulting from this treatment-related hair loss may impact therapy success. To date, no elective preventive treatment is available to patients. Induction of a conserved protective response, the so-called stress protein response, was shown by many laboratories to protect various types of cultured cells against killing by essentially all classes of anti-neoplastic agents currently in clinical use. The present proposal will test in animal models the hypothesis that prior localized induction of the stress protein response in mitotically active cells of (scalp) hair follicles will protect these cells against killing by cyclophosphamide, adriamycin, etoposide, taxol and vincristine, resulting in the prevention of alopecia. Localization of the induction of the stress protein response will ensure that the preventive treatment will not interfere with the cytotoxic activity of the anti-neoplastic agents in cells other than those of hair follicles, i.e., that the preventive treatment of alopecia will not diminish chemotherapy efficacy.