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Modulation of Murine Radiation-induced Fibrosarcoma-1 Tumor Metabolism and Blood Flow in Situ via Glucose and Mannitol Administration Monitored by ³¹P and ²H Nuclear Magnetic Resonance Spectroscopy¹

Department of Chemistry, Washington University, St. Louis, Missouri 63130 [Y. C. H., S-G. K., J. J. H. A.], and Division of Hematology and Oncology, Department of Internal Medicine [J. L. E.] and Department of Radiation Oncology [M. S.], Wayne State University School of Medicine, Detroit, Michigan 48201

The hyperglycemia-induced in situ metabolism and blood flow changes produced in s.c. implanted murine radiation-induced fibrosarcoma-1 tumors, grown on the flanks of female C3H/HeJ mice, were examined with ³¹P and ²H nuclear magnetic resonance. Initial experiments verified a hyperglycemic tumor acidification similar to that reported earlier with a different substrain of mice, C3H/AnF (J. L. Evelhoch et al., Proc. Natl. Acad. Sci. USA, 81: 6496–6500, 1984). Changes in the tumor pH, phosphorus metabolites, and blood flow were then compared after administration of saline, glucose, or mannitol (a nonmetabolizable glucose analogue) using a mole-equivalent dose of the sugars (i.e., 0.8 mmol/20g mouse). Neither saline (n = 8) nor mannitol (n = 6) administration had any marked effect upon tumor pH, whereas glucose administration produced a mean maximum tumor pH reduction of 0.74 ± 0.09 (SE; n = 9) during the 2.5 h post-glucose injection. No significant changes in high energy phosphate concentrations were observed during the same period after saline injection. After glucose injection, the [phosphocreatine] gradually decreased by 64% (P = 0.0001). After the initial 1 h post-glucose injection, the [inorganic phosphate] increased by 58% (P = 0.0001), and the [nucleoside triphosphates] decreased by 29% (P = 0.0001) during the following 1.5 h. After mannitol injection, while there was no change in [inorganic phosphate] over time (P = 0.37), the [phosphocreatine] decreased by 33% (P = 0.0001) and the [nucleoside triphosphates] decreased by 21% (P = 0.0015) within 20 min, then both the [phosphocreatine] and [nucleoside triphosphates] remained at constant levels during the following 2 h. In parallel experiments, the volumetric rate of tumor blood flow and perfusion was measured by ²H nuclear magnetic resonance monitoring of ²H₂O washout kinetics (S-G. Kim and J. J. H. Ackerman, Cancer Res., 48: 3449–3453, 1988); tumor blood flow decreased by 80% (P = 0.0001, n = 11), 60% (P = 0.0031, n = 4), and 20% (P = 0.058, n = 10) at 2 h after glucose, mannitol, or saline injections, respectively. These results suggest that anaerobic glycolysis is a requirement for hyperglycemic tumor acidification. However, the decrease in tumor blood flow accompanying hyperglycemic acidification suggests that flow reduction also may be a contributing or a required cofactor for acidification via inhibition of lactic acid egress. These blood flow reductions are consistent with an observed increase in systemic hematocrit, by 8% (40–48%) or 10% (41–51%) during 2 h post-glucose or mannitol injection, which is expected to cause an increase in systemic as well as local tumor blood viscosity.

¹ Support for this work was provided by NIH Grants CA-40411 and GM-30331, and National Science Foundation Instrument Grant CHE-8100211.

² Present address: Kettering-Scott Magnetic Resonance Laboratory, Kettering Medical Center and Department of Biochemistry, Wright State University School of Medicine, 3535 Southern Boulevard, Kettering, OH 45429.

³ Present address: Department of Chemistry, University of Washington, Seattle, WA 98195.

⁴ To whom requests for reprints should be addressed, at Department of Chemistry, Campus Box 1134, Washington University, One Brookings Drive, St. Louis, MO 63130.

Received 6/ 6/89. Accepted 4/ 1/91.

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