Timing of hypertonic glucose and thermochemotherapy with 1-(4-amino-2-methylpyrimidine-5-yl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) in the BT4An rat glioma: relation to intratumoral pH reduction and circulatory changes after glucose supply.
OBJECTIVE
Intraperitoneal hypertonic glucose has previously been shown to induce hyperglycemia, hemo-concentration, and to influence systemic and tumor circulation, and, thus, enhance the effect of thermochemotherapy with 1-(4-amino-2-methylpyrimidine-5-yl)methyl-3-(2-chloroethyl)-3-nitrosoure a (ACNU) and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). However, the optimal timing and the precise mechanisms responsible are not known. The effect of different time intervals between glucose load and thermochemotherapy with ACNU in the treatment of BT4An tumors, therefore, was investigated. Changes of serum glucose (Se-glucose), hemoglobin, systemic circulation parameters, tumor pH, and tumor temperature, induced by intraperitoneal glucose and/or hyperthermia, were measured to assess their effect on tumor growth.


METHODS
(a): Inbred BD IX rats with BT4An tumors on the hind leg were treated with ACNU 7 mg/kg intravenously just before waterbath hyperthermia, and intraperitoneal hypertonic glucose (6 g/kg) at different time intervals before (240-0 min) or immediately after thermochemotherapy. (b): Intratumoral pH and temperature were measured at different intervals after intraperitoneal glucose, and during hyperthermia with or without previous glucose. (c): Hemoglobin, hematocrit, and Se-glucose were measured at different times after intraperitoneal glucose. (d): Mean arterial pressure, pulse pressure, and heart rate were measured for 120 min after intraperitoneal glucose.


RESULTS
(a): The number of tumor controls and the growth delay was greatest with glucose 45 min before thermochemotherapy, and least with a time interval of 240 min. Glucose after thermochemotherapy delayed tumor growth. (b): After intraperitoneal glucose alone, intratumoral pH decreased gradually from 6.76 to 5.86 after 240 min. Hyperthermia 120 min after glucose induced a rapid further pH drop, while hyperthermia alone had no significant influence on pH. Intratumoral temperature was higher during hyperthermia in animals given glucose. (c): A substantial rise of Se-glucose and hemoglobin developed. The hemoconcentration was maintained also after reduction of Se-glucose towards normal values. (d): An initial tachycardia, and a reduction of the mean arterial pressure of about 10% 5-45 min after was measured.


CONCLUSIONS
The data indicate that a complex interaction between gradually reduced tumor pH, hyperglycemia, hemoconcentration, and reduced tumor blood flow, and not a breakdown of systemic circulation, is responsible for the effect of intraperitoneal glucose on thermochemotherapy with ACNU. Interestingly, enhancement of thermochemotherapy effect was also seen when intraperitoneal glucose was given after heat and ACNU.
Schem
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BC
Department of Oncology, Haukeland Hospital, University of Bergen, Norway.
Roszinski
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S
Krossnes
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BK
Mella
O
O
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002330:Carmustine / Q000493:pharmacokinetics / Q000627:therapeutic use; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D005909:Glioblastoma / Q000737:chemistry / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D005950:Glucose Solution, Hypertonic / Q000008:administration & dosage* / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D006979:Hyperthermia, Induced; D015376:Nimustine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005950:Glucose Solution, Hypertonic; D015376:Nimustine; D002330:Carmustine