Effect of hypertonic glucose in thermotolerant rat BT4An gliomas treated with combined hyperthermia and BCNU in vivo.

The influence of hypertonic glucose i.p. on development of thermotolerance and thermochemosensitivity with BCNU in thermotolerant tumours, and on intratumoural pH alterations in previously unheated and thermotolerant tumours, was investigated in BT4An tumours grown on the hind foot of BD IX rats. Thermotolerance was induced with local waterbath hyperthermia (44 degrees C/45 min) 24 h before start of test treatment. Hypertonic glucose immediately after priming hyperthermia did not inhibit development of thermotolerance, despite a significant reduction of pH by glucose. The pH reduction was less in thermotolerant tumours. Glucose administered before treatment of thermotolerant tumours did not change the growth rate of tumours treated with hyperthermia (44 degrees C/45 min), BCNU (20 or 25 mg/kg i.p.) or thermochemotherapy with a low or high dose BCNU (10 or 20 mg/kg), in contrast to previous results, where glucose enhanced thermochemosensitivity of non-thermotolerant tumours.

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.

PURPOSE: 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 AND MATERIALS: (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. CONCLUSION: 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.

Hyperthermia enhances mitoxantrone cytotoxicity on human breast carcinoma and sarcoma xenografts in nude mice.

In this preclinical in vivo study, we measured antitumor response, local side effects and systemic toxicity of locally applied water-bath hyperthermia given alone or simultaneously with mitoxantrone (3 mg/kg b.w. i.v.; LD 10) on a human derived breast carcinoma (MX 1) or a human sarcoma (S 117) transplanted to female athymic (nude) mice. A single hyperthermia treatment at a tumor temperature up to 43 degrees C for 1 hr caused in both tumor lines only minor tumor regressions and transient tumor growth delay. However, the antitumor effect of mitoxantrone was significantly enhanced by local hyperthermia at 42 degrees C and particularly at 43 degrees C. In both tumor lines complete tumor regressions were achieved only if mitoxantrone was combined with hyperthermia. Undesired side effects and drug toxicity were not enhanced by hyperthermia. According to in vitro data and the results of the present in vivo study mitoxantrone seems to be a good candidate for clinical trials in combination with locoregional hyperthermia.

Local hyperthermia enhances cyclophosphamide, ifosfamide and cis-diamminedichloroplatinum cytotoxicity on human-derived breast carcinoma and sarcoma xenografts in nude mice.

Antitumour response and toxicity of locally applied hyperthermia with or without cyclophosphamide, ifosfamide, and cis-diamminedichloroplatinum (cisplatin) have been compared. The model systems were human breast carcinoma (MX1/3) and human sarcoma (S117) grown in nude mice. In order to detect changes of tumour oxygenation intratumoral PO2 and pH were measured before, during and following hyperthermia. In both human tumour lines a monotherapy with one of the cytotoxic drugs or with hyperthermia caused a transient growth delay, while the combination of the same dose of the drugs with hyperthermia (at 43 degrees C for 1 h) resulted in complete tumour remissions. During hyperthermia, in both tumour types oxygenation was improved. Intratumoral pH remained practically unchanged.

Effects of hyperthermia and/or hyperglycemia on pH and pO2 in well oxygenated xenotransplanted human sarcoma.

The heat-induced interdependent changes of tumor blood flow, pO2, and pH decisively influence the therapeutic effect of hyperthermia (HT). This fact has induced us to determine simultaneously the frequency distribution of local pO2 values and the intratumoral pH in a xenotransplanted human sarcoma cell line at a normal blood glucose level and under hyperglycemic conditions before, during, and after HT. Two groups, one of 10 and one of 9 congenitally athymic nude rats with a subcutaneously implanted S117 human sarcoma into the right hind paw (mean tumor volume 5.3 cm3) were treated with local waterbath HT (tumor temperature 43 degrees C, 1 hr) alone or in combination with i.p. glucose injections (6 g/kg, 2 hr before the onset of HT). Tumor oxygenation remained improved throughout HT. Tumor pH did not decrease during HT. Hyperglycemia alone elicited a decrease of intratumoral pH and pO2, probably mainly due to hemoconcentration. The additional warming of the tumors (43 degrees C) during hyperglycaemia did not further decrease pO2 and pH. Silver stained sections of the tumors showed only a few very small necrotic areas, even in tumors of volumes up to 8 cm3. Our results indicate a well oxygenated tumor. In contrast to most tumors studied so far, hyperthermia in this tumor induces not only an initial increase of oxygenation but a lasting elevation of mean tumor pO2 for the duration of HT (up to 60 min).