A moderate elevation of blood glucose level increases the effectiveness of thermoradiotherapy in a rat tumor model. I. Relative contributions of glucose and heating to tumor acidification.
OBJECTIVE
To establish dose-effect relationships for tumor acidification induced by heat and glucose as a basis for testing the value of adding glucose administration to combined heat and x-ray treatment at clinically achievable glucose and temperature levels.


METHODS
Rhabdomyosarcoma BA1112 was grown s.c. in the upper leg of 16-20-week-old Wag/Rij rats. Animals were given 2 consecutive 100-min periods of saline (S) or glucose (G) infusion, while keeping tumor temperature at 37 degrees, 42 degrees, or 43 degrees C for 1 or 2 periods, in various combinations, each involving 6 animals. Glucose was infused i.v. as a 20% solution at 2.4-3 g/kg/h. Tumors were heated using 2,450-MHz electromagnetic radiation, and tumor pH was measured using a 0.7 mm fiberoptic probe.


RESULTS
Mean overall baseline pH was 7.00 (SD 0.10). The change induced by G37G43 (i.e., glucose infusion for a full 200 min, first 100 min at 37 degrees C, final 100 min at 43 degrees C) was -0.48 +/- 0.03 (SEM) pH units, and -0.17 +/- 0.03 for S37S43. The effect of G37G42 was -0.37 +/- 0.03 pH units, compared with -0.08 +/- 0.02 for S37S42 and -0.28 +/- 0.04 for glucose alone (G37G37). Glucose was less effective when given after or fully parallel to heating: -0.21 +/- 0.02 pH units for S43G37 and -0.37 +/- 0.02 for G43G43.


CONCLUSIONS
The glucose-induced tumor pH drop is much more pronounced than that induced by heat, both of which are dose dependent. The effects of glucose and heat seem additive if heating is started when glucose-induced acidification has reached its plateau level, but the overall effect is diminished if administration is fully simultaneous or in reversed order. Schedule G37G43 is optimal with respect to tumor acidification. Its predicted superiority in thermoradiotherapy as compared with S37S42, S37S43, and G37G42 treatment regimens was confirmed in a subsequent experimental tumor control study.
van den Berg
A P
AP
Department of Radiation Oncology, University Hospital Rotterdam-Daniel, Rotterdam, The Netherlands. berg@rtth.azr.nl
van den Berg-Blok
A E
AE
Kal
H B
HB
Reinhold
H S
HS
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D006979:Hyperthermia, Induced; D051381:Rats; D012208:Rhabdomyosarcoma / Q000378:metabolism* / Q000532:radiotherapy / Q000628:therapy*
D001786:Blood Glucose; D005947:Glucose