Preservation of the chemical architecture of a cell or of an organism under changing and perhaps stressful conditions is termed homeostasis. An integral feature of homeostasis is the rapid expression of genes whose products are specifically dedicated to protect cellular functions against stress. One of the best known mechanisms protecting cells from various stresses is the heat-shock response which results in the induction of the synthesis of heat-shock proteins (HSPs or stress proteins). A large body of information supports that stress proteins--many of them molecular chaperones--are crucial for the maintenance of cell integrity during normal growth as well as during pathophysiological conditions, and thus can be considered "homeostatic proteins." Recently emphasis is being placed on the potential use of these proteins in preventing and/or treating diseases. Therefore, it would be of great therapeutic benefit to discover compounds that are clinically safe yet able to induce the accumulation of HSPs in patients with chronic disorders such as diabetes mellitus, heart disease or kidney failure. Here we show that a novel cytoprotective hydroxylamine derivative, [2-hydroxy-3-(1-piperidinyl) propoxy]-3-pyridinecarboximidoil-chloride maleate, Bimoclomol, facilitates the formation of chaperone molecules in eukaryotic cells by inducing or amplifying expression of heat-shock genes. The cytoprotective effects observed under several experimental conditions, including a murine model of ischemia and wound healing in the diabetic rat, are likely mediated by the coordinate expression of all major HSPs. This nontoxic drug, which is under Phase II clinical trials, has enormous potential therapeutic applications.

The heat-shock protein Hsp90 has been shown to be essential for the functional integrity of the telomerase complex. The telomerase activity is enhanced in melanoma and stabilizes the chromosomal integrity in proliferating cells. Furthermore, overexpression of Hsp90 induces silencing of point mutations in transcription factors which, otherwise, would result in a loss-of-function phenotype. In melanocytic lesions there is a higher risk of mutations caused by the enhanced proliferation in melanocytic cells. By analyzing microdissected melanocytic tumors by semiquantitative PCR, we demonstrate an overexpression of Hsp90 mRNA in malignant melanomas (10/14) and in melanoma metastases (6/6) as well as in melanoma cell lines (9/9) when compared with melanocytic nevi (2/9). These results could be confirmed on protein level by immunohistochemistry. While melanocytic nevi show discrete Hsp90 expression only in a minor fraction (2/9), malignant melanomas and metastases show a positive Hsp90 immunohistochemistry in the majority of cases; (7/9) and (13/14), respectively. In addition, by analyzing melanoma metastases by flow cytometry we show that Hsp90 is expressed on the surface of tumor cells (7/8). From these data we conclude that Hsp90 is present in advanced malignant melanomas and may have a stabilizing effect on the cellular functions in proliferating cells of melanocytic lesions and could thereby be a prerequisite for the tumor progression. As Hsp90 is expressed on the cell surface, it might also be a potential immunorelevant target structure for immunotherapy of melanoma.

With excellent cure rates and a good tolerability profile, terbinafine should continue to be a drug of choice for the treatment of toenail onychomycosis in the rising number of NIDDM patients receiving multiple medication.

No abstract

Cell membrane localization of the 72 kDa heat shock protein 70 (Hsp70) has been found on different tumour cell lines, on biopsy material from solid tumours and metastases and on leukaemic blasts from acute myelogenous leukaemia patients, but not on the corresponding normal tissues, as determined by flow cytometry using the Hsp70-specific monoclonal antibody C92F3B1. In the present study Hsp70 membrane expression was studied on primary malignant melanomas, melanoma metastases, melanocytes, human skin fibroblasts and peripheral blood lymphocytes, together with expression of the melanoma-associated markers Mel-1, Mel-2 and Mel-5, major histocompatibility complex class I and the fibroblast-specific marker ASO2. As previously shown, fibroblasts and peripheral blood lymphocytes from healthy human volunteers were found to be negative for Hsp70 and for the melanoma-associated markers Mel-1, Mel-2 and Mel-5. Human melanocytes from healthy human donors were also negative for Hsp70, but were positive for Mel-1 and Mel-5. Independent of the Clark's level, all the malignant melanomas (n = 9) and metastases (n = 11) exhibited were positive for both Mel-1 and Mel-2. The primary melanomas could be divided into two groups according to their Hsp70 and Mel-5 expression pattern: those with an Hsp70-negative and a Mel-5-positive phenotype (-/+) (five out of nine), and those with an Hsp70-positive and a Mel-5-negative phenotype (+/-) (four out of nine). All the melanoma metastases (n = 11) had an Hsp70-positive, Mel-5-negative phenotype (+/-). These data provide the first hint that the marker combination Hsp70 positive/Mel-5 negative might be useful in estimating the metastatic potential of a melanoma. Investigations on changes in the marker combination Hsp70/Mel-5 during onset of melanoma disease and progression will clarify its potential as a prognostic risk factor.