Disruption of cellular energy balance by suramin in intact human prostatic carcinoma cells, a likely antiproliferative mechanism.

The antiparasitic drug, suramin, has antiproliferative effects in human carcinoma cells. It has been suggested that this occurs through blockade of growth factor-receptor interactions. Three types of evidence that suramin rapidly inhibits cellular respiration or disrupts cellular energy balance in intact cells of the human prostate carcinoma cell line, DU145, are presented. Beginning at approximately 10(-4) M, suramin rapidly causes dose-dependent inhibition of tetrazolium conversion by mitochondrial dehydrogenases in intact cells, demonstrating an inhibition of respiration. This effect is reversed by exchange with suramin-free media but not by pretreatment with serum, epidermal growth factor, insulin-like growth factor I, acidic and basic fibroblast growth factors, or calcium. Rhodamine 123 (10 micrograms/ml) uptake by mitochondria in intact DU145 cells is inhibited in the presence of 10(-3) M suramin. Treatment with 10(-4)-10(-3) M suramin causes the loss of rhodamine 123 from cells with mitochondria prestained with rhodamine 123, indicating that suramin is acting as an ionophore or respiratory poison. Also shown by electron microscopy are progressive toxic changes in mitochondria of DU145 cells within 1 h after treatment with 10(-4) M suramin. These data indicate that in intact DU145 cells 10(-4) M suramin rapidly disrupts cellular energy balance or respiration as seen by three studies of mitochondrial state. Disruption of energy balance or respiration represents a likely antiproliferative mechanism, as is thought to be a primary mechanism for the action of suramin in parasitic diseases. This proposed mechanism of action for suramin can explain the most prominent observed clinical toxicities of nephrotoxicity, adrenal toxicity, coagulopathy, and demyelinating neuropathy.     

A case study in planning for public health education: the organ and tissue donation experience.

The chasm between the supply and demand of donated organs and tissues continues to grow despite widespread public awareness of transplantation and numerous efforts to educate the public about organ donation. It is fast becoming a significant public health problem in this country. The need for more effective public education is well documented in the literature on transplantation and is a primary objective of organizations in the transplant field. In response to this need, the Division of Organ Transplantation in the Health Resources and Services Administration of the Public Health Service initiated a project to examine the nature and scope of donation education initiatives throughout the country, to identify shortcomings, and to suggest ways the Federal Government could contribute to the effectiveness of public education in organ and tissue donation. The project resulted in the development of a protocol that also is applicable to other health education programs. Its major steps consisted of assessing the status of donation-related public education in the United States, identifying existing needs in donation education by applying principles learned from other public health education programs, and identifying roles that could be assumed to help strengthen the American public''s commitment to organ and tissue donation. These roles, which could be adopted by an transplant-related organization, were as broker of knowledge, producer of educational strategies, energizer through communications research, and catalyst by bringing together other groups. This approach to needs assessment and planning may provide useful insights both for those concerned with transplants and for professionals conducting education campaigns related to other public health issues.     

Immunohistochemical localization of glutathione-S-transferase and glutathione peroxidase in adult Syrian hamster tissues and during kidney development.

Tissues from adult Syrian hamsters were studied with immunoperoxidase techniques using polyclonal antibodies to glutathione-S-transferase (rat liver and human placental enzymes) and human erythrocyte glutathione peroxidase. Most tissues immunostained similarly with these antibodies. Most notable was the cytoplasmic staining of mesenchyme tissues, especially smooth muscle, by all three antibodies. Epithelial cells stained distinctively, but usually less intensely than mesenchyme. Epithelial cells from all levels of the gastrointestinal tract, respiratory epithelium, transitional epithelium, and epidermis all showed strong staining with these antibodies. Other epithelial cell types were usually positive but showed less dramatic staining. Most epithelial tissues showed both nuclear and cytoplasmic staining; some also showed cell-surface (eg, cilia) staining. The role of these enzymes in cell differentiation of a stable organ was studied by immunostaining the kidney during its development. Early stroma (13- and 15-day fetuses) of the kidney (metanephric mesenchyme) showed strong cell-surface staining for glutathione transferases and moderate staining for glutathione peroxidase; renal tubules (which are epithelial cells) at this stage were negative for these markers. As renal tubules differentiated, first cytoplasm and then nuclei stained moderately, suggesting that glutathione-S-transferases and glutathione peroxidase are markers of both mesenchymal cells, including embryonic mesenchyme, and terminal differentiation of at least some epithelial cells.     

Correlates of cell-mediated immunity in Candida albicans-colonized gnotobiotic mice.

Germfree athymic (nu/nu) and euthymic (nu/+) mice were colonized with a pure culture of Candida albicans. Correlates of cell-mediated immunity (lymphocyte proliferation and footpad responses to C. albicans antigens) and in vivo clearance of mucosal infections were assessed at different time intervals after alimentary tract colonization. C. albicans hyphae infected the dorsal surface of the tongue and the cardial section of the stomach in both nu/nu and nu/+ mice within 1 week after colonization with a pure culture of C. albicans. With time after colonization and infection with C. albicans, nu/+ mice manifested positive lymphocyte proliferation and positive footpad responses to Candida antigens that appeared to correlate with the capacity to clear Candida hyphae from the dorsal surface of the tongue and in the stomach. Conversely, nu/nu mice could not clear mucosal candidosis (in the stomach and on the tongue) and did not manifest either lymphocyte proliferation or footpad swelling in response to C. albicans antigens. These studies indicated that T-cell-mediated immunity may play a role in the acquired resistance of mice to mucosal candidosis. Since neither nu/nu nor nu/+ mice developed a progressive systemic disease, T cells apparently do not play a prominent role in murine resistance to systemic candidosis of endogenous origin.     

Early epidermal destruction with subsequent epidermal hyperplasia is a unique feature of the papilloma-independent squamous cell carcinoma phenotype in PKCepsilon overexpressing transgenic mice

Protein kinase C epsilon (PKCepsilon) overexpressing transgenic (PKCepsilon Tg) mice develop papilloma-independent squamous cell carcinomas (SCC) elicited by 7,12-dimethylbenz[a]anthracene (DMBA) tumor initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA) tumor promotion. We examined whether epidermal cell turnover kinetics was altered during the development of SCC in PKCepsilon Tg mice. Dorsal skin samples were fixed for histological examination. A single application of TPA resulted in extensive infiltration of polymorphonuclear neutrophils (PMNs) into the epidermis at 24 h after TPA treatment in PKCepsilon Tg mice while wild-type (WT) mouse skin showed focal infiltration by PMNs. Complete epidermal necrosis was observed at 48 h in PKCepsilon Tg mice only; at 72 h, epidermal cell regeneration beginning from hair follicles was observed in PKCepsilon Tg mice. Since the first TPA treatment to DMBA-initiated PKCepsilon Tg mouse skin led to epidermal destruction analogous to skin abrasion, we propose the papilloma-independent phenotype may be explained by death of initiated interfollicular cells originally destined to become papillomas. Epidermal destruction did not occur after multiple doses of TPA, presumably reflecting adaptation of epidermis to chronic TPA treatment. Prolonged hyperplasia in the hair follicle may result in the early neoplastic lesions originally described by Jansen et al. (2001) by expanding initiated cells in the hair follicles resulting in the subsequent development of SCC.