NUCLEOSIDE TRANSPORTERS AS CHEMOPREVENTION TARGETS

University Of Tennessee Health Sci Ctr, Memphis TN

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Abstract

DESCRIPTION (provided by applicant): An estimated 555,500 people in the United States will die from cancer this year. Cancer cost to the United States' economy was $156 billion in 2001. The gravity of the situation is compounded by the fact that most cancers (especially solid tumors) have no cure. This underscores the importance of cancer prevention. This research proposal is intended to investigate the targeting of nucleoside transporters as a novel approach to cancer prevention. Nucleoside transporters are the means by which mammalian cells take up preformed nucleosides which can serve as precursors to nucleotides that are used in DNA and RNA synthesis by cells. The overexpression of nucleoside transporters has been demonstrated in some tumors, as well as a correlation between nucleoside transporter expression and cell proliferation rates. It has recently been observed that the anticarcinogenesis activity of agents like dehydroepiandrosterone (DHEA) can be reversed by the presence of extracellular nucleosides, suggesting that nucleoside transport (NT) inhibitors can at least augment the anticarcinogenesis activity of chemopreventive agents such as DHEA, or could be chemopreventive drugs on their own. Starving precancerous cells of these vital building blocks might attenuate their growth and facilitate their elimination by the bodies natural defense systems such as immune surveillance, before they can become established cancers. Although NT inhibitors have already been shown to be potentially useful for combination chemotherapy with anticancer drugs such as 5-fluorouracil, their potential as cancer prevention agents has not been explored. Studies have also shown that tamoxifen, an anti-estrogen chemopreventive agent against breast cancer in high-risk populations, does inhibit nucleoside transport and also downregulates nucleoside transporter gene expression, suggesting a possible link between NT inhibition and the chemoprevention action of the drug. This proof-of-concept research project will investigate the role of nucleoside transport inhibition in modulating the effects of chemopreventive agents like DHEA and tamoxifen, in the in vitro JB6 cell mouse epidermal carcinogenesis, and in vivo mammary carcinogenesis models, respectively. Nucleoside transport inhibitors, namely, nitrobenzylthioinosine, dipyridamole and dilazep, as well as novel inhibitors will be used in these studies. These inhibitors will be used in the carcinogenesis models, as well as JB6 P+/AP-1-luciferase and P+/NF-kB-luciferase reporter cells treated with tumor promoters (TPA or analogs), in the presence or absence of DHEA or tamoxifen and/or physiological ribonucleosides (RNs) and deoxyribonucleosides (DRNs). The results of the proposed experiments will provide further mechanistic insights into the carcinogenesis process that may lead to the identification of novel molecular targets for chemoprevention. The targeting of nucleoside transporters for cancer prevention is a new idea, the success of which will have significant scientific impact, and possible health and economic benefits, as well as advance research into carcinogenesis and the cancer prevention arena