The present Project contributes to the fundamental goal of the Program to exploit the acidified microenvironment of the tumor as a means for sensitizing tumor cells to hyperthermia. It is designed to test the hypothesis that the potentiation in heat-induced cell killing achieved after acute acidification is mediated in part by an abrogation of cell cycle checkpoints that are normally activated by heat damage in cells kept under normal pH. The focus is on the molecular characterization of a checkpoint activated in S-phase in cells exposed to high temperatures. Although it has long been known that exposure of cells to hyperthermia causes a strong inhibition of DNA replication, our laboratory is the first to provide evidence that this inhibition is associated with processes equivalent to the activation of a checkpoint in S-phase. It is generally thought that abrogation of checkpoints potentiates the toxic consequences of the inducing damage. The experimental design aims at the molecular characterization of the S-phase checkpoint and the evaluation of acute acidification as a means to overcome it. Novel preliminary data allow us to formulate a model for the regulation of DNA replication in heated cells, and the first set of Specific Aims is designed to systematically test its postulates. The second set of Specific Aims is designed to characterize t the molecular level the basis of its abrogation by acute acidification, and to apply this information to the treatment of human tumors using protocols specific to the Program. Key role in the proposed experiments plays an in vitro assay for eukaryotic DNA replication, the Simian virus 40 (SV40) based in vitro DNA replication assay. We propose to test first a model postulating that heat-induced damage in chromatin structures induces regulatory pathways equivalent to check point activation that inhibit DNA replication by transacting-processes. This inhibition of DNA replication is at the level of replicon initiation and is considered independent of direct inhibition via cis-acting processes resulting from chromatin damage, or inhibition caused by heat-induced deregulation of the enzymatic machinery. The latter processes are thought to inhibit predominantly chain elongation. The results of the proposed experiments are expected to shed light on the role of checkpoint activation in heat sensitivity and to elucidate its molecular determinants, as well as the mechanism of its abrogation by acute acidification. The studies will ultimately enhance our understanding of heat sensitization in an acidotic environment, and may allow the definition of new targets for intervention by means of physiological modifications in the tumor, or by means of drugs preventing the activation of these checkpoints. Such intervention may further improve the efficacy of hyperthermia in the management of human tumors.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Thomas Jefferson University
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Coss, Ronald Allen; Storck, Christopher W; Wells, Tiffany C et al. (2014) Thermal sensitisation by lonidamine of human melanoma cells grown at low extracellular pH. Int J Hyperthermia 30:75-8
Li, Lin Z; Zhou, Rong; Leeper, Dennis B et al. (2011) ³¹P-MRS studies of melanoma xenografts with different metastatic potential. Adv Exp Med Biol 701:69-73
Xu, He N; Zhou, Rong; Nioka, Shoko et al. (2009) Histological basis of MR/optical imaging of human melanoma mouse xenografts spanning a range of metastatic potentials. Adv Exp Med Biol 645:247-53
Li, Lin Z; Zhou, Rong; Xu, He N et al. (2009) Quantitative magnetic resonance and optical imaging biomarkers of melanoma metastatic potential. Proc Natl Acad Sci U S A 106:6608-13
Sonveaux, Pierre; Vegran, Frederique; Schroeder, Thies et al. (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 118:3930-42
Li, Lin Z J; Zhou, Rong; Zhong, Tuoxiu et al. (2007) Predicting melanoma metastatic potential by optical and magnetic resonance imaging. Adv Exp Med Biol 599:67-78
Chi, Sulene L; Wahl, Miriam L; Mowery, Yvonne M et al. (2007) Angiostatin-like activity of a monoclonal antibody to the catalytic subunit of F1F0 ATP synthase. Cancer Res 67:4716-24
Fang, Jun; Quinones, Quintin J; Holman, Trevor L et al. (2006) The H+-linked monocarboxylate transporter (MCT1/SLC16A1): a potential therapeutic target for high-risk neuroblastoma. Mol Pharmacol 70:2108-15
Adams, David J; Wahl, Miriam L; Flowers, James L et al. (2006) Camptothecin analogs with enhanced activity against human breast cancer cells. II. Impact of the tumor pH gradient. Cancer Chemother Pharmacol 57:145-54
Coss, Ronald A (2005) Inhibiting induction of heat shock proteins as a strategy to enhance cancer therapy. Int J Hyperthermia 21:695-701

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