**3.1. Selection by Warburg's effect (conductivity selection)**

24 Hyperthermia

The oncological hyperthermia application, which uses the nano-scale heating technology (called oncothermia, [160]); the radiofrequency (RF) current flows through the chosen volume of the body (see Figure 22.), heating up the cell-membrane individually (see Figure 23.). The cell-membrane is a good isolator and so the current is most dense at the extracellular electrolyte in the immediate vicinity of the cells. Of course, when the absorbed energy is too much, the individual cellular-heating does not work, all the volume will be equally heated. This is again the declaration of the well- known rule: "the difference

**Figure 22.** Both electrodes are always active, independently of its size or form. The current starts in one

**Figure 23.** The selection mechanism of the optimally applied RF-current targets the cellular membrane,

Generally, a certain power interval is necessary for optimal efficacy, both the too high and the too low are non-optimal. The cars form a trivial example: the cold engine needs more fuel to be heated up for its optimal use, but it must be cooled down and kept in a definite

The average heating cannot produce high-efficacy. The high efficacy requests high selectivity for the accurate control of the process. The simple control of the average wastes a part of energy. This "waste" is expended energizing the particles, which are not involved in the desired process. The particles in the targeted process, which would like to have more power for the actual effect, have also the average only. Simple examples could be quoted from the everyday life again: when I would like to honor somebody's excellent work, it would be inefficient to honor everybody in average, being sure that the person whom the

The proper selection has to choose not only the cells in general from the heated volume, but especially the malignant cells have to be selected from the target. This task could be solved using the specialties of malignant cells in comparison with their healthy counterparts.

and ends on the other. The energy density is different, and many safety functions differ

between the poison and the medicament is only their dose".

concentrates the energy in nano-range of the cell

range of temperature by a cooling system for its optimal work.

honor is due is also among the members of the group.

As Otto Warburg discovered, the malignant cells behave completely differently from their healthy counterparts, [161], having mitochondrial dysfunction to produce ATP. (For this discovery a Nobel-prize was granted for him.) Warburg's work nowadays has its renaissance [162], [163]; showing the validity of the dominance of non-mitochondrial (fermentative) way of ATP production. The fermentative way of the metabolic ATP production is anyway "ancient" chemical reaction, which was characteristic at the beginning of the evolution of life, when the oxygen, the general electron acceptor was available only in a small amount in the atmosphere. It is the fermentative way to utilize the energy of glucose converting it into lactic acid (*CH3CHOHCOOH*), producing only 2 ATPs in one cycle.

The metabolism in healthy cells is mainly governed by the convertible energy-source of ATP. The citrate (Krebs) cycle by mitochondria, the "energy plant" in cells, produces 36 ATPs with excellent efficacy with the help of oxygen (see Figure 24/a.). The fermentative ATP production is a low efficacy process in malignant cells, (see Figure 24/b.*),* however, (due to its simplicity) it can occur in large amount, its overall energy-flux can be higher than obtained from the high efficacy process.

**Figure 24.** Differences in healthy and malignant cells

The malignant cells are in frequent and permanent cellular-division. The energyconsumption for the intensive division is higher than the energy requirement for the healthy cells in homeostasis. This is available only when the glucose intake is at least 18 times higher, because its ATP production is 18 times less than normal. This allows the cell to supply energetically all the normal processes and make the differentiation and development, the adaptation and evolution possible. This is a huge additional part of the glucose influx to the anyway high Warburg process. The higher glucose metabolism can be measured by positron emission tomography (PET) [164]. When we take the higher

reproduction (proliferation) rate of malignant cells into account, (which requests more energy than for the cells in homeostasis), the final products ("waste") are produced intensively. Hence, these cells are surrounded by "waste" compounds, their extracellular electrolyte is denser in ions, and the pH in their vicinity is lower. Consequently, the higher metabolism increases the ion-transport and the ion-concentration in the area of the malignant cell, which lowers the impedance (gains the conductivity) of that volume. This irregular behavior can be measured and imaged by the Electric Impedance Tomography (EIT), [165]. One of the applications of this effect can be applied even in the prophylactics like mammography [166].

Local Hyperthermia in Oncology – To Choose or not to Choose? 27

 The increase of the current density in the tumor can be visualized by the RF-CDI (radiofrequency current density image), which is a definite, MRI-conducted

**Figure 25.** Effective and automatic focusing of oncothermia is a strong selective factor of the tumor and

Together with these effects, further add-ons are expected by oncothermia: the intensive heat transfer on the cellular membrane intensifies the ionic-transports [179], which (in positive feedback) changes the ionic motility and conductivity. In addition, the gain of the blood perfusion by the increasing temperature (below 39 oC) will lower the impedance (increase the conductance) [92], [180] which is an additional positive feedback selectivity at the beginning of the treatment. In the advanced cases, the blood-perfusion is increased by the neo-angio-genesis [181]. This extra perfusion (generally till T=39 oC) lowers the impedance

The positive feedback of growing temperature effectively increases the conductivity, [182]. The measured gain of the selectivity is 2% in oC, [183], which is in the range of 3643 oC,

The living material is not an ordered solid. Contrary to the crystals [184], it is hard to introduce the co-operation. The living matter is in aqueous solution, which is mostly well ordered, nearly crystalline (semi-crystalline, [185]) in the living state. This relative order formed the "dilute salted water" into the system having entirely different mechanical, chemical, physical, etc. behaviors from the normal aqueous solutions. Indeed, the important role in the living systems of the so-called ordered water was pointed out in the middle of the

(increases the conductivity), which is again a selectivity factor.

**3.2. Selection by Szent-Gyorgyi's effect (dielectric selection)** 

measurement of the real processes, [175], [176], [177], [178].

the malignant cells

that is 14% increase.

In consequence of the physical differences, the malignant cells are distinguishable by their biophysical parameters; their electric properties differ from normal. The main differences are:


The conductance (as a self-selective factor choosing optimal current path, see Figure *25.*) ranges from 20% to 4000% difference between the healthy and malignant tissues. The data sporadically fluctuate, but generally the tumor has lower impedance than its healthy counterpart does! This is exactly what is used in the oncothermia technique.

There are numerous proofs of the conductive selection.


 The increase of the current density in the tumor can be visualized by the RF-CDI (radiofrequency current density image), which is a definite, MRI-conducted measurement of the real processes, [175], [176], [177], [178].

26 Hyperthermia

like mammography [166].

healthy counterpart [169].

and its charge-distribution also deviates [168].

reproduction (proliferation) rate of malignant cells into account, (which requests more energy than for the cells in homeostasis), the final products ("waste") are produced intensively. Hence, these cells are surrounded by "waste" compounds, their extracellular electrolyte is denser in ions, and the pH in their vicinity is lower. Consequently, the higher metabolism increases the ion-transport and the ion-concentration in the area of the malignant cell, which lowers the impedance (gains the conductivity) of that volume. This irregular behavior can be measured and imaged by the Electric Impedance Tomography (EIT), [165]. One of the applications of this effect can be applied even in the prophylactics

In consequence of the physical differences, the malignant cells are distinguishable by their biophysical parameters; their electric properties differ from normal. The main differences are: The efficacy of the ATP production in the cancerous cell is low. The large ATP demand for the proliferative energy-consumption allows less ATP for active membrane stabilization by K+ & Na+ transport, so the membrane potentiating weakens [167]. The cellular membrane of cancerous cells differ electrochemically also from the normal

The membrane of the cancerous cell differs in its lipid and sterol content from their

 The membrane-permeability is changed by the above differences. In consequence of these, the efflux of the K+, Mg++ and Ca++ ions increase, while the efflux of Na+ decreases together with the water-transport from the cell. Therefore, the cell swallows, and its membrane potential decreases further [170]. (The efflux of K+ regulates the pH of the cell, takes the protons out from the cytosol). The concentration of Na+ increases in the cytosol, and parallel to this, the negative ion-concentration also grows on the glycocalix shell, decreasing the membrane potential and the tumor will be negatively polarized on average, [171]. This fact was well used for direct current treatment

The conductance (as a self-selective factor choosing optimal current path, see Figure *25.*) ranges from 20% to 4000% difference between the healthy and malignant tissues. The data sporadically fluctuate, but generally the tumor has lower impedance than its healthy

 In a simple theoretical investigation [173] an elliptical "tumor" is introduced into an otherwise homogeneous body. Making use of the appropriate Green's function, the changes in conductivity between the tumor and the surrounding region can be

 A precise diagnostics has been established by careful calculation of electric impedance of human thorax as well [174], and the 3-D electrical impedance tomography is

(electro-chemical cancer therapy (ECT)) by Nordenstrom and others. The conductivity (σ) of the tumor tissue will be higher than normal, [172].

counterpart does! This is exactly what is used in the oncothermia technique.

There are numerous proofs of the conductive selection.

determined.

intensively studied, [165].

**Figure 25.** Effective and automatic focusing of oncothermia is a strong selective factor of the tumor and the malignant cells

Together with these effects, further add-ons are expected by oncothermia: the intensive heat transfer on the cellular membrane intensifies the ionic-transports [179], which (in positive feedback) changes the ionic motility and conductivity. In addition, the gain of the blood perfusion by the increasing temperature (below 39 oC) will lower the impedance (increase the conductance) [92], [180] which is an additional positive feedback selectivity at the beginning of the treatment. In the advanced cases, the blood-perfusion is increased by the neo-angio-genesis [181]. This extra perfusion (generally till T=39 oC) lowers the impedance (increases the conductivity), which is again a selectivity factor.

The positive feedback of growing temperature effectively increases the conductivity, [182]. The measured gain of the selectivity is 2% in oC, [183], which is in the range of 3643 oC, that is 14% increase.
