Factors controlling oxygen utilization.
We demonstrate, theoretically, that oxygen diffusion distance is related to the metabolic rate of tumors (QO2) as well as the oxygen tension. The difference in QO2 rate between tumors can vary by as much as 80-fold. Inhibition of oxygen utilization by glucose or chemical inhibitors can improve the diffusion distance. Combining respiratory inhibitors with increased availability of oxygen will further improve the oxygen diffusion distance for all tumors. A simple means for inhibiting oxygen consumption is the use of glucose (the Crabtree effect). The inhibition of tumor oxygen utilization by glucose occurs in R323OAc mammary carcinoma and 9L glioma cells. However, stimulation of oxygen consumption is observed with glucose in the Q7 hepatoma cell line. MIBG, a known inhibitor of oxygen utilization, blocks oxygen consumption in 9L, but is weakly inhibitory with the Q7. Q7 tumor cells demonstrate an anomalous behavior of glucose and MIBG on oxygen consumption. Our results clearly demonstrate the necessity for comparing effects of different agents on different tumor cells. Generalizations cannot be made with respect to the choice of inhibitor for in vivo use. Our work shows that oxygen consumption also can be inhibited with malonate and chlorosuccinate. These substrates may be effective in vivo, where glucose is low and glutamine is the major substrate. Our results indicate that information about individual tumor substrate-linked metabolic controls may be necessary before attempting to inhibit oxygen utilization in vivo for therapeutic benefit.
Biaglow
John
J
Dewhirst
Mark
M
Leeper
Dennis
D
Burd
Randy
R
Tuttle
Steve
S
D019797:3-Iodobenzylguanidine / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D004058:Diffusion; D005260:Female; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D005973:Glutamine / Q000494:pharmacology; D008314:Malonates / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D019802:Succinic Acid / Q000494:pharmacology
D008314:Malonates; D005973:Glutamine; D019797:3-Iodobenzylguanidine; C030290:malonic acid; D019802:Succinic Acid; D005947:Glucose