DNA damage produced by combined hyperglycemia and hyperthermia in two mouse fibrosarcoma tumors in vivo.

In this study we used alkaline elution to examine DNA damage produced in two murine fibrosarcomas after hyperthermia (42 degrees C), with or without preinduced hyperglycemia. The work was stimulated by a recent report that pretreatment of mice with glucose prior to hyperthermia decreased the growth rate in a similar fibrosarcoma tumor. The intercellular tumor pH dropped from its resting value of 7.1 to a value of 6.6 at 1.5 hr after a single injection of glucose. While treatment with either glucose alone or heat alone produced very little detectable damage, the combination of these two agents resulted in marked degradation of tumor DNA isolated immediately after treatment. DNA degradation was accompanied by a simultaneous decrease in cell viability; thus, direct cell killing and subsequent nuclease or lysosomal enzyme activity are probably involved. We also tested whether hyperglycemia combined with hyperthermia influenced the DNA-DNA crosslinking induced by subsequent cyclophosphamide (Cy) treatment. Because of the extensive degradation caused by the pretreatment alone under the conditions used in these initial experiments, we were not able to quantitate with validity the amount of Cy-induced crosslinking. However, damage in viable cells may presumably interact with the subsequent Cy treatment to produce further selective cell killing in the tumor.