hyperthermia in the clinical oncology

The following effects of hyperthermia could play a very important role in overcoming MDR:
1. Increased membrane fluidity and permeability, disorganisation of membrane lipids, increase of intracellular cytostatics penetration and antigenity of cells (HSP).
2. Membrane and cytoplasmic protein denaturation.
3. Altered DNA conformation.
4. Inhibition of DNA repair (through disturbance of the functions of genes products involved in DNA damage recognition and repair).
5. In the tumour tissue after hyperthermia and hyperglycemia occur deterioration of blood flow and microcirculation, hypoperfusion, hypoxy and anoxy, lactic acid accumulation, pH extracellular <7, substrate and ATP depletion.
6. Disturbance of normal cell functions: gene transcription, expression, signaling followed induction of apoptosis.
(Istomin J. & Bogovic J. 1989; Hettinga J. 1997) see tables.
Status of tumour supressor genes play very important role in the hyperthemia efficacy. Expression of wtp53 increases thermosensitivity in murine fibroblasts (transfected with wtp53) by about 200% (Matsumoto 1996).
Hyperthermia is one of the strongest modifiers of chemotherapy see table.
Antitumour activity of 5-FU, verapamil (MDR modulator) and hyperthermia against human adenocarcinoma cells in vitro was very convincing (Shchepotin et al.1997) see table.

Apoptosis: genetically programmed cell death

Apoptosis plays a variable role in the response of tumours to mild hyperthermia. While in some tumours apoptosis could not enchanced at all, or only marginally enchanced by heating, in others almost 100% of cells died by this process within a few hours of treatment (Bogovic 1990). The original mediator of apoptosis is unknown, but probably involves intracellular changes that either directly induce apoptosis or cause the cell to undergo apoptosis as a secondary response to the induced damage. A number of physiological and nonphysiological signals can induce the apoptotic program, and there are similarities in the pathways by which these different inducers transmit their signal to the cell. The susceptibility of tumours cells to programmed cell death is influenced by a series of different proto-oncogens and tumour-supressor genes (see MDR )

Effects of Hyperthermia

(Bogovic J. 1989, Mod. Hettinga J. 1997, Vaupel P.W. 1997)

The influence of the hyperthermia on the efficiency of different cytostatics

Activity of 5-FU, Verapamil & Hyperthermia Against Human Adenocarcinoma Cells in vitro
Shchepotin IB et al. 1997

Possibilities of modification of hyperthermia
in the complex treatment of malignant neoplasmas

Biochemical predisposition for hyperthermia efficacy

Ability of tumor cells to intensify anaerobic glycolysis (metabolism of glucose till lactic acid). Tumour tissue is normaly slightly acidic. Sensitization of tumours to hyperthermia caused by low pH is not obvious in cells under chronic acidosis. It is necessary to induce acute acidosis for sensitizing cells to hyperthermia. Intensification of glycolysis by glucose infusion. Decrease of pH in tumour tissue.

Mechanism of lowering pH by artificial hyperglycemia and its therapeutic potential

Local mechanism: the increased glucose (G) level enhances the production of lactic acid through anaerobic glycolysis in tumours.
Systemic mechanism: after G administration cardiac output decreases and then tumour blood flow (TBF) to tumours consequently decreases (more than 50%). G increases the rigidity of the erythrocyte membrane and raises blood viscosity. Erythrocytes with rigid membrane are easily trapped in capillaries in tumours, this also contributes to the decrease of TBF. The decrease of TBF results in the delayed excretion of the lactic acid from the tumour. An increase in lactate concentration in a tumour decreases pH further, and the lowered pH will increase the rigidity of erythrocyte membrane Therapeutic potential: induction of acute acidosis, hypoperfusion, hypoxy and anoxy. Result: sensitizing cells to hyperthermia.

Influence on artificial hyperglycemia efficacy Istomin J. & Bogovic J. 1992

More intensive increase of lactic acid concentration and decrease of pH was observed in cells suspension of W-256, slightest in Sa-45. In vivo the results were just the opposite: 300% elevation of lactic acid in Sa-45 1 h after AHH (604 vs 175 nm/mg in control), 200% after 7 days and minimal changes in W-256 were registrated. Complex analysis of microcirculation in tumours reveals a different blood flow inhibition. It depends on functional activity of tumour vessels and type of microcirculation in tumour tissue.Typical for W-256 is a central type of blood flow, extensive arteria and veins through the tumour node. That supports brisk evacuation of lactic acid from tumour tissue. pH decrease and tumour damage were not distinct. Sa-45 has a peripheric type of microcirculation. Tumour damage mainly in the centre of node was observed already 3 h after AHH. The decrease of pH was more demonstrative and clearly perceptible in this tumour.

Change of Lactic Acid Concentration in SCCVII Tumours
after AHH in vivo
Hirokawa K. et al. 1997

G -Glucose, HT - hyperthermia, AHH - artificial hyperglycemia

Continue with clinical experience

1984-2002 J. Bogovic Cancer Research.