Experimental and Clinical Therapeutics

Monday, October 17, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP161) Characterization of the glucose metabolism in xenotransplanted human squamous cell carcinomas.

Quennet, Verena*,1, Walenta, Stefan1, Zips, Daniel2, Yaromina, Ala2, Baumann, Michael 2, Mueller-Klieser, Wolfgang1, 1 Institute of Physiology and Pathophysiology, Mainz, RLP, Germany2 Department of Radiotherapy and Oncology, Medical Faculty, Dresden, RLP, Germany

ABSTRACT- In a multiinstitutional project, including scientific groups at the universities of Dresden, Mainz, Muenchen and Wuerzburg the relevance of the glucose metabolism in malignancies for the radiosensitivity is to be investigated. In the laboratory at Dresden 10 different tumor lines of head and neck squamous cell carcinoma (HNSCC) with different radiosensitivities are grown in nude mice (nu/nu). Cryosections and/or fragments of the tumors are then sent to the different participating institutions. The research team in Mainz determines the local concen-tration of ATP, glucose and lactate in cryosections by imaging bioluminescence. The expres-sion level of LDH-A and GLUT1 is examined by quantitative RT-PCR. Furthermore, immun-histochemical stainings, such as anti-mouse, anti-carbonic anhydrase IX and anti-HIF 1 are performed in adjacent sections. Anti-mouse serves as structural analysis to discriminate tumor from host tissue, CA IX is suggested to label hypoxic regions. Using computerized image analysis the various distributions are overlayed and tested for possible correlations. Three established cell lines with different radiobiological properties have been studied up to now with bioluminescence imaging with regard to their glycolytic metabolism. Respective mean (± SD) tissue concentrations (mol/g) of metabolites in FaDu, UTSCC15, and UTSCC14 tumors are: for glucose 0.94±0.99, 2.54±1.72, and 2.95±1.36, for ATP 1.43±0.91, 2.54±1.11, and 2.05±0.56, and for lactate 16.85±9.77, 15.11±7.87, and 11.85±2.73. Compared to corresponding data from clinical tumors, the metabolic concentrations in the xenografts are higher with the exception of the glucose concentration in FaDu tumors. It is obvious that the xenografts show an inverse correlation between lactate and glucose. Tissue concentrations of glucose and lactate exhibit pronounced intra- and intertumoral variations and are indicative of an extremely large turnover rate in one relatively radioresistant tumor line (FaDu). This is in accordance with the working hypothesis of a high glycolytic flux being correlated with radio-resistance, among other reasons, due to the radical scavenger function of pyruvate. (Supported by the Deutsche Forschungsgemeinschaft: grant # Mu 576/14-1)

Key words: glucose metabolism, radiosensitivity, glycolytic enzymes, glycolytic flux

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2005 RRS