Browsing by Author "Keller, Eric J."

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    Characterization of Thermally Activated Metalloenediyne Cytotoxicity in Human Melanoma Cells
    (BioOne, 2018-08) Keller, Eric J.; Porter, Meghan; Garrett, Joy E.; Varie, Meredith; Wang, Haiyan; Pollok, Karen E.; Turchi, John J.; Zaleski, Jeffrey M.; Dynlacht, Joseph R.; Radiation Oncology, School of Medicine
    Enediynes are a highly cytotoxic class of compounds. However, metallation of these compounds may modulate their activation, and thus their cytotoxicity. We previously demonstrated that cytotoxicity of two different metalloenediynes, including (Z)-N,N'-bis[1-pyridyl-2-yl-meth-(E)-ylidene]octa-4-ene-2,6-diyne-1,8-diamine] (PyED), is potentiated when the compounds are administered to HeLa cells during hyperthermia treatment at concentrations that are minimally or not cytotoxic at 37°C. In this study, we further characterized the concentration, time and temperature dependence of cytotoxicity of PyED on human U-1 melanoma cells. We also investigated the potential mechanisms by which PyED cytotoxicity is enhanced during hyperthermia treatment. Cell killing with PyED was dependent on concentration, temperature during treatment and time of exposure. Potentiation of cytotoxicity was observed when cells were treated with PyED at temperatures ≥39.5°C, and enhancement of cell killing increased with temperature and with increasing time at a given temperature. All cells treated with PyED were shown to have DNA damage, but substantially more damage was observed in cells treated with PyED during heating. DNA repair was also inhibited in cells treated with the drug during hyperthermia. Thus, potentiation of PyED cytotoxicity by hyperthermia may be due to enhancement of drug-induced DNA lesions, and/or the inhibition of repair of sublethal DNA damage. While the selective thermal activation of PyED supports the potential clinical utility of metalloenediynes as cancer thermochemotherapeutic agents, therapeutic gain could be optimized by identifying compounds that produce minimal toxicity at 37°C but which become activated and show enhancement of cytotoxicity within a tumor subjected to localized hyperthermic or thermal ablative treatment, or which might act as bifunctional agents. We thus also describe the development and initial characterization of a novel cofactor complex of PyED, platinated PyED (Pt-PyED). Pt-PyED binds to DNA-like cisplatin, and much like PyED, cytotoxicity is greatly enhanced after treatment with the drug at elevated temperatures. However, in contrast to PyED, Pt-PyED is only minimally cytotoxic at 37°C, at concentrations at which cytotoxicity is enhanced by hyperthermia. Further development of cisplatin-based enediynes may result in compounds which, when activated, will possess multiple DNA binding modalities similar to cisplatin, but produce less side effects in tissues at normothermic temperatures.
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    Ethical Considerations Surrounding Survival Benefit-Based Liver Allocation
    (Office of the Vice Chancellor for Research, 2013-04-05) Keller, Eric J.; Helft, Paul R.; Kwo, Paul Y.
    The disparity between the demand for and supply of donor livers has continued to grow over the last two decades, placing greater weight on the need for efficient and effective allocation. Although the use of extended criteria donors (ECD) has shown greater potential, it remains unregulated. Schaubel et al. have recently proposed a survival benefit model which balances waitlist survival and potential transplantation benefit for a given quality of donor liver. The OPTN/UNOS Liver and Intestinal Organ Transplantation Committee considered this and other models in a recent report, concluding that the current allocation method does not require modification. In order to further evaluate the survival benefit model, the various ethical concerns shaping organ allocation were discussed and used to identify strengths and shortcomings associated with the proposed model. Compared to the current MELD/PELD system, the survival benefit model incorporates a greater number of ethical principles, uses a sophisticated statistical model to increase efficiency and reduce waste, minimizes bias, and parallels developments in the allocation of other organs. Conversely, the model fails to address quality of life concerns, prioritization for younger patients, its less promising posttransplant prediction accuracy, and potential issues regarding informed consent and economic burdens. To remedy these issues, we suggested incorporating various improvements based on recent literature. Although limitations exist, the survival benefit model now exists as a better means of improving allocation. We support the model proposed by Schaubel et al., with the amendments we suggested, and urge the OPTN/UNOS Liver and Intestinal Organ Transplantation Committee and the transplant community to strongly consider this model as another step toward better liver allocation.