The effect of fenofibrate, a ligand of peroxisome proliferator-activated receptor (PPAR) alpha, on the growth and metastatic potential of Bomirski hamster melanoma s.c. tumors, pigmented line (BHM Ma) was investigated in vivo. RT-PCR and Western-blot analyses revealed the presence of mRNA and protein of PPAR alpha in BHM Ma cells. The animals treated orally with fenofibrate developed significantly fewer metastatic foci in the lungs, as compared to the control group; however, primary tumor growth remained unaltered. This observation is interesting in respect of the potential use of fenofibrate in melanoma chemoprevention.
We characterized the melanogenic apparatus in a family of transplantable gerbil melanomas (melanotic and amelanotic) using a combination of biophysical, ultrastructural and biochemical methods. Melanotic melanomas produced pure eumelanin but in vesiculo-globular melanosomes ('pheomelanosomes'); the eumelanosomes, characteristically ellipsoidal in shape with fibrillar or fibrillo-lamelar matrix, were never noticed. Melanotic melanomas also had significant tyrosinase activity and Zn, Pb/S, Ca and P content; all higher than in the amelanotic variants. The amelanotic variant, which was devoid of melanin pigment and melanosomes, had clearly detectable tyrosinase activity (albeit at 20% of that in the melanotic variant). Thus, with these multidirectional approaches we demonstrate that pure eumelanin can be synthesized in organelles ultrastructurally defined as pheomelanosomes, but a defect in the formation of melanosomes can prevent in vivo melanin synthesis despite the presence of detectable tyrosinase activity. We conclude that this melanoma system provides an excellent experimental model for the study of molecular components determining pheo- and/or eumelanogenesis. The information generated can be used for defining the roles of melanogenesis and of tyrosinase expression in the regulation of melanoma behavior and the effect of their modification on the course of the disease.
The effect of the presence of melanin on the response of mammalian cells to ionizing radiation was investigated in a model system utilizing the ability of Chinese hamster ovary cells to incorporate melanin by endocytosis. Cells were incubated in monolayer cultures from 2 to 20 hours with melanin prepared from 'beef eye' or synthesized by air oxidation of 3,4-dihydroxyphenylalanine. For asynchronous cultures, the survival curve parameters for cells incubated with both types of melanin were indistinguishable from those of the same cells without added melanin. The radiation response to fractionated doses of 6 Gy separated by various periods did not indicate any effect of melanin on the extent or kinetics of repair of sublethal damage. Likewise, the repair of potentially lethal damage in plateau phase cultures was unaffected by the presence of melanin. Thus the explanation for the clinical radiation resistance of melanomas in the absence of a direct radiation effect might more likely be found in consideration of other factors such as the role of melanin in oxygen consumption or in differentiation.
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