Hyperthermia is a rapidly developing treatment method in oncology.

The classical effect is based on well-focused energy absorption

targeting the malignant tissue.

Unfortunately, the heat-shock protein (HSP) synthesis may considerably

suppress the treatment’s efficiency, causing cells to adapt

and survive the shock. Electro-hyperthermia heats the targeted tissue

by means of electricity, producing less HSP in the cells than classical

hyperthermia.

The main improvement is keeping the energy absorption within

the extracellular matrix (ECM). By heating the ECM, ion-mobility

increases, metabolic rates increase, and the heat destroys the cells’

membrane before the heat-shock activates the intra-cellular HSP

mechanisms

Szász, András

Szász, Nóra

Szász, Olivér

English

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		 119Electro-hyperthermia in OncologyO. Szasz1, N. Szasz2 and A. Szasz1, 31Group Biotech. Fac. Engineering, Szent Istvan University, Gödöllõ, Hungary2Div. Bioeng., Massachusetts Institute of Technology, Cambridge, MA, U.S.A.3Faculty of Engineering, Strathclyde University, Glasgow, United KingdomSummaryHyperthermia is a rapidly developing treatment method in oncol-ogy.The classical effect is based on well-focused energy absorptiontargeting the malignant tissue.Unfortunately, the heat-shock protein (HSP) synthesis may con-siderably suppress the treatment’s efficiency, causing cells to adaptand survive the shock. Electro-hyperthermia heats the targeted tissueby means of electricity, producing less HSP in the cells than classi-cal hyperthermia.The main improvement is keeping the energy absorption withinthe extracellular matrix (ECM). By heating the ECM, ion-mobilityincreases, metabolic rates increase, and the heat destroys the cells’membrane before the heat-shock activates the intra-cellular HSPmechanisms.1. IntroductionThere are intensive discussions in scientific communities on themechanism of oncological hyperthermia. The number of conferencesand journals on the subject has escalated.The increasing number of applications and clinical trials at uni-versities, clinics, hospitals and institutes prove the feasibility and120 	 2. Effects of HyperthermiaSome well-established milestones can help summarize the effectsof hyperthermia:1. At the increase of the temperature, the blood supply of tumorsdecreases while that of healthy tissue increases. [13 ].2. As the metabolism of tumors is very intensive, it is usually warmerthan healthy tissues. [14 ].3. There is not enough oxygen available for the metabolism of malignanttissues; resulting in hypoxia and anaerobe metabolism, which inturn produces acidosis. [15 ].4. Increased metabolism significantly depletes the ATP stores of thecells, resulting in increased apoptosis. [15].5. DNA replication can often be blocked by heat, therefore slowingdown cell division. [16 ].6. Hyperthermia complements ionizing radiation:applicability of clinical hyperthermia in cancer therapies. Some ofthese are summarised below.121  	7. The chemo-therapies also can be complemented by hyperthermia8. Hyperthermia has significant pain-reduction and few side effects.[17 ].9. Hyperthermia enhances the efficiency of the immune system [16].3. Heat Shock Protein ProductionHSPs (stress- or heat-shock-proteins) are highly conserved pro-teins, which are vital in almost every living cell [18 ]. Stresses acti-vate their synthesis [19 ], and HSPs help cells accommodate to newchallenges. HSPs are present in all cancerous cells helping them toadapt to stresses and help tumor-cells survival. Moreover HSPs areinduced by all treatments. This generally provides effective protec-tion of the cells against apoptosis [20 ] and can lead to a multi-drugresistance [21 ].4. Electro-HyperthermiaElectro-hyperthermia is devoted to enhance the efficiency of con-ventional hyperthermia by additional, mainly thermally induced, non-thermal effects, and the aim of suppressing the existing disadvan-tages of classical thermal treatments. Its advantage is that electri-cally-coupled energy of certain frequencies are primarily absorbed inthe ECM, as it is not able to penetrate through the membrane (Fig.1.).The temperature gradient from the ECM to the cell creates atremendous heat-flow (1500 nW/mm2) through the membrane. Thisis well above the natural metabolic heat-flow of 20 nW/mm2. Moreo-ver, the high temperature gradient (1 K/mm) forces membrane cur-rents of approximately 150 pA/mm2, which is dominantly caused by122 	 Na+ influx. In addition, the thermal flux increases intracellular pres-sure to 1.32 MPa. The membranes of a significant percent of malig-nant cells are rigid [22 ], and cannot protect against this increasedpressure.These processes lead to the cell membrane damage of the malignantcells before the heat reaches the cell-nuclei, and could induce HSPsynthesis and adaptation to the new stress. However, membrane HSPsare induced by the extreme heat at the membrane. These supportapoptotic signals and help eliminate the malignant cells in a naturalfashion.The developed system is technically and medically certified bythe European Standards according to the Medical Device Directive.5. ConclusionsHyperthermia is one of the effective modalities in oncology. Itsimproved version, electro-hyperthermia, is highly selective, gentleand safe, providing all the positive effects of classical hyperthermiawith the additional advantages of:1) reobtained apoptotic signal,2) blocked angiogenesis,3) blocked HSP synthesis within the cell, thus no heat toleranceor other shock resistance can develop.The successful operation of electro-hyperthermia systems is inprogress in various clinics and hospitals.Fig.1. The RF current flows extracellularly123  	References[1] Emami B, Scott C, Perez CA, Asbell S, Swift P, Grigsby P, MontesanoA, Rubin P, Curran W, Delrowe J, Arastu H, Fu K, Moros E.: Int J RadiatOncol Biol Phys 1996 Mar 15;34(5):1097-1104[2] Harima Y, Nagata K, Harima K, Ostapenko VV, Tanaka Y, Sawada S.L.Int J Hyperthermia 2001 Mar;17(2):97-105[3] Harima Y, Nagata K, Harima K, Oka A, Ostapenko VV, Shikata N,Ohnishi T, Tanaka Y.:.Cancer 2000 Jan 1;88(1):132-138[4] Kitamura K, Kuwano H, Watanabe M, Nozoe T, Yasuda M, SumiyoshiK, Saku M, Sugimachi K.J: Surg Oncol 1995 Sep;60(1):55-58.[5] Overgaard J, Gonzalez Gonzalez D, Hulshof MC, Arcangeli G, Dahl O,Mella O, Bentzen SM.: Lancet 1995 Mar 4;345(8949):540-543[6] Shchepotin IB, Evans SR, Chorny V, Osinsky S, Buras RR, MaligonovP, Shabahang M, Nauta RJ.: Surg Oncol 1994 Feb;3(1):37-44[ 7] Sherar M, Liu FF, Pintilie M, Levin W, Hunt J, Hill R, Hand J, VernonC, van Rhoon G, van der Zee J, Gonzalez DG, van Dijk J, Whaley J,Machin D.: Int J Radiat Oncol Biol Phys 1997 Sep 1;39(2):371-380[8] Sneed PK, Stauffer PR, McDermott MW, Diederich CJ, Lamborn KR,Prados MD, Chang S, Weaver KA, Spry L, Malec MK, Lamb SA, VossB, Davis RL, Wara WM, Larson DA, Phillips TL, Gutin PH.: Int J RadiatOncol Biol Phys 1998 Jan 15;40(2):287-295[9] Egawa S, Tsuliyama I, Watanabe S, Ohno Y, Morita K, Tominaga S,Onoyama Y, Hashimoto S, Yanagawa S, Uehgara S, Abe M, MochizuliS, Sugiyama A, Inoue T: J. 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Electro-hyperthermia in Oncology

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