The effect of a mixture of vitamins in modifying the efficacy of commonly used drugs in the treatment of human melanoma has not been studied. Vitamin C and d-alpha-tocopheryl succinate (alpha-TS) alone reduced the growth of human melanoma (SK-30) cells in culture, whereas beta-carotene (BC), 13-cis-retinoic acid (RA), or sodium selenite alone was ineffective. RA caused morphological changes, as evidenced by flattening of cells and formation of short cytoplasmic processes. A mixture of four vitamins (vitamin C, BC, alpha-TS, and RA) was more effective in reducing growth of human melanoma cells than a mixture of three vitamins. The growth-inhibitory effect of cis-platin, decarbazine, tamoxifen, and recombinant interferon-alpha 2b was enhanced by vitamin C alone, a mixture of three vitamins (BC, alpha-TS, and RA), and a mixture of four vitamins (vitamin C, BC, alpha-TS, and RA) that contained 50 micrograms/ml of vitamin C. These data show that a mixture of three or four vitamins can enhance the growth-inhibitory effect of currently used chemotherapeutic agents on human melanoma cells.
Carbohydrate intake, preference, and taste thresholds may be altered in current and former cigarette smokers, which may mediate weight gain and risk for obesity in individuals who quit smoking. Attempts to model these effects in rodents have primarily used noncontingent nicotine administration. The purpose of this research was to characterize changes in chow and sucrose intake in rats during a 23-h access model of i.v. nicotine self-administration (NSA), in which rats lever-pressed for chow, sucrose, and nicotine under concurrent fixed-ratio (FR) 1 schedules. Male rats were assigned to one of three groups that differed in food and drug availability. The Nicotine C+S group had concurrent access to nicotine, chow, and sucrose. The Saline C+S group had access to saline, chow, and sucrose. The Nicotine C-Only group had access to nicotine and chow, but not sucrose. Changes in food intake and weight gain were assessed during baseline, NSA, and nicotine withdrawal (i.e., saline extinction). Weight gain was significantly slowed during NSA and increased during withdrawal, but did not differ between the nicotine groups. NSA produced a significant decrease in both chow and sucrose intake. Gradual tolerance to nicotine’s effects on sucrose, but not chow intake, occurred. During withdrawal, chow and sucrose intake increased, with a larger percent increase in sucrose intake compared to chow. The proportion of total food intake from sucrose was greater at the end of withdrawal compared to baseline, indicating a history of nicotine intake changed dietary preference. Combined, these results indicate that sucrose intake is more resistant to nicotine’s appetite suppressant effects and withdrawal from nicotine produces a greater increase in sweet food intake alongside general increases in chow intake. Changes in overall food intake in current and ex-smokers may lead to increased risk for obesity and other health problems, potentially limiting the benefit of quitting smoking.
Pluripotent cells have been reported to exhibit lower frequencies of point mutations and higher levels of DNA repair than differentiated cells. This predicts that pluripotent cells are less susceptible to mutagenic exposures than differentiated cells. To test this prediction, we used a lacI mutation-reporter transgene system to assess the frequency of point mutations in multiple lines of mouse pluripotent embryonic stem cells and induced pluripotent cells, as well as in multiple lines of differentiated fibroblast cells, before and after exposure to a moderate dose of the mutagen, methyl methanesulfonate. We also measured levels of key enzymes in the base excision repair (BER) pathway in each cell line before and after exposure to the mutagen. Our results confirm that pluripotent cells normally maintain lower frequencies of point mutations than differentiated cells, and show that differentiated cells exhibit a large increase in mutation frequency following a moderate mutagenic exposure, whereas pluripotent cells subjected to the same exposure show no increase in mutations. This result likely reflects the higher levels of BER proteins detectable in pluripotent cells prior to exposure and supports our thesis that maintenance of enhanced genetic integrity is a fundamental characteristic of pluripotent cells.
Pluripotent stem cells hold the potential to form the basis of novel approaches to treatment of disease in vivo as well as to facilitate the generation of models for human disease, providing powerful avenues to discovery of novel diagnostic biomarkers and/or innovative drug regimens in vitro. However, this will require extensive maintenance, expansion, and manipulation of these cells in culture, which raises a concern regarding the extent to which genetic integrity will be preserved throughout these manipulations. We used a mutation reporter (lacI) transgene approach to conduct direct comparisons of mutation frequencies in cell populations that shared a common origin and genetic identity, but were induced to undergo transitions in cell fate between pluripotent and differentiated states, or vice versa. We confirm that pluripotent cells normally maintain enhanced genetic integrity relative to that in differentiated cells, and we extend this finding to show that dynamic transformations in the relative stringency at which genetic integrity is maintained are associated with transitions between pluripotent and differentiated cellular states. These results provide insight into basic biological distinctions between pluripotent and differentiated cell types that impact genetic integrity in a manner that is directly relevant to the potential clinical use of these cell types.
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