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 spectroscopy.
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.(ABSTRACT TRUNCATED AT 400 WORDS)
Hwang
Y C
YC
Department of Chemistry, Washington University, St. Louis, Missouri 63130.
Kim
S G
SG
Evelhoch
J L
JL
Seyedsadr
M
M
Ackerman
J J
JJ
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002245:Carbon Dioxide / Q000097:blood; D003903:Deuterium; D005260:Female; D005354:Fibrosarcoma / Q000098:blood supply / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D006400:Hematocrit; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008353:Mannitol / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D009381:Neoplasms, Radiation-Induced / Q000098:blood supply / Q000378:metabolism*; D010100:Oxygen / Q000097:blood; D010313:Partial Pressure; D010725:Phosphocreatine / Q000378:metabolism; D010758:Phosphorus; D012039:Regional Blood Flow / Q000187:drug effects; D012265:Ribonucleotides / Q000378:metabolism; D012513:Sarcoma, Experimental / Q000098:blood supply / Q000378:metabolism*
D001786:Blood Glucose; D012265:Ribonucleotides; D010725:Phosphocreatine; D002245:Carbon Dioxide; D010758:Phosphorus; D008353:Mannitol; D003903:Deuterium; D005947:Glucose; D010100:Oxygen