Cancer research
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The health-related effects of interactions between reactive oxygen species (ROS) and dietary antioxidants and the consequences of dietary antioxidant supplementation on human health are by no means clear. Although ROS, normal byproducts of aerobic metabolism, are essential for various defense mechanisms in most cells, they can also cause oxidative damage to DNA, proteins, and lipids, resulting in enhanced disease risk. Dietary antioxidants (e.g., vitamin E, vitamin C, beta-carotene, and selenium), as well as endogenous antioxidant mechanisms, can help maintain an appropriate balance between the desirable and undesirable cellular effects of ROS. ⋯ Some data suggest antioxidants can ameliorate toxic side effects of therapy without affecting treatment efficacy, whereas other data suggest antioxidants interfere with radiotherapy or chemotherapy. Overall, examination of the evidence related to potential interactions between ROS and dietary antioxidants and effects on human health indicates that consuming dietary antioxidant supplements has pros and cons for any population and raises numerous questions, issues, and challenges that make this topic a fertile field for future research. Overall, current knowledge makes it premature to generalize and make specific recommendations about antioxidant usage for those at high risk for cancer or undergoing treatment.
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p53 transgenic mice carrying a dominant negative mutation were crossed with Ink4A/Arf heterozygous-deficient mice to investigate whether there is a synergy between these two germ-line mutations in promoting carcinogen-induced lung tumor progression in mice. Mice with a p53 dominant negative mutation and Ink4A/Arf heterozygous deficiency exhibited >20-fold increase in tumor volume compared with approximately 4-fold increase in Ink4A/Arf heterozygous-deficient mice and a 9-fold increase in mice with only the p53 dominant negative mutation. The effect of Ink4A/Arf heterozygous deficiency on lung tumor progression occurred late in the carcinogenesis process (>30 weeks after carcinogen treatment). ⋯ Thus, mutant mice with alterations in p53 and/or Ink4A/Arf exhibited a significant resistance to chemoprevention by budesonide. Because p53 and Ink4a/Arf mutations are the most prevalent mutations in human lung cancers, the effectiveness of chemopreventive agents on the mutant A/J mice containing alterations with p53 and Ink4a/Arf is the best preclinical estimate of their efficacy in humans. Thus, the mutant A/J mouse model should prove useful for chemoprevention studies.
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Indole-3-carbinol (I3C), autolysis product of glucosinolates present in cruciferous vegetables, has been indicated as a promising agent in preventing the development and progression of breast cancer. I3C has been shown to inhibit the growth of human cancer cells in vitro and possesses anticarcinogenic activity in vivo. Because I3C is unstable and may be converted into many polymeric products in the digestive tract, it is not yet clear whether the biological activity observed can be attributed to I3C or some of its polymeric products. ⋯ Contrarily to CDK6, the level of CDK4, the other kinase involved in the G(1) phase of the cell cycle, remains unchanged. Interestingly, the tetramer resulted about five times more active than I3C in suppressing the growth of human breast cancer cells. On the whole, our data suggest that the I3C tetrameric derivative is a novel lead inhibitor of breast cancer cell growth that may be a considered a new, promising therapeutic agent for both ER+ and ER- breast cancer.
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We constructed a single-chain anti-gp240 antibody (designated MEL sFv) and fused this to the recombinant toxin gelonin (rGel). MEL sFv-rGel was produced in bacterial expression plasmid (pET-32), and the protein composition was confirmed by both DNA sequencing and Western analysis. Inhibition of cell-free protein synthesis by the fusion construct demonstrated an IC(50) of 100 pM, comparable with that for native gelonin (104 pM). ⋯ Groups of tumor-bearing nude mice were treated with fusion toxin at either 2 or 20 mg/kg. Compared with saline-treated controls, for which mean tumor burden increased 6-fold, the groups treated with the high and low doses of fusion construct showed no increase or only a 2-fold increase, respectively. These studies suggest that this recombinant fusion construct has potent cytotoxic activity both in vitro and in vivo and is an excellent candidate for clinical development.
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Pituitary adenomas cause significant morbidity caused by compression of regional structures or the inappropriate expression of pituitary hormones. However, little is known about the molecular changes that contribute to the development of these tumors. To investigate these changes, we recently used cDNA microarray analysis to identify several genes with altered expression patterns in pituitary adenomas. ⋯ Comparison of protein and specific [(3)H] folic acid binding levels in subtypes of NF adenomas suggested that the immunohistochemically negative adenomas produced more properly folded FRalpha than adenomas that stained positively for anterior pituitary hormones. Finally, immunohistochemistry demonstrated that FRalpha was specifically expressed in NF adenoma cells. These results demonstrate that overexpression of FRalpha mRNA by NF pituitary adenomas results in production of properly folded FRalpha protein, may mediate vitamin transport, and could potentially facilitate the growth of these tumors.