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Rationale for Clinical Use of Heat

The effect of heat on malignant tumors was first mentioned by Hippocrates. In 1866, Busch [ref: 30] described the disappearance of a soft tissue sarcoma after high fever in a patient with erysipelas. Later, Coley [ref: 40] induced fever by injecting bacterial toxins; Warren [ref: 412] and Westermark [ref: 422] used localized hyperthermia to produce tumor regression in patients.

In the past 20 years interest has been rekindled in the clinical application of heat, encouraged by biologic reports that there may be a significant advantage in the use of heat combined with radiation and cytotoxic drugs to enhance the killing of tumor cells. [ref: 57,59,65] The clinical use of heat has been hampered by a lack of adequate equipment to effectively deliver heat in deep-seated and even large superficial lesions and of thermometry techniques that provide reliable information on heat distribution in the target tissues. However, significant progress has been made. [ref: 134,187]

In vitro and in vivo biologic experiments suggest that heat may be more damaging to tumors than to normal tissues for several reasons: chronically hypoxic cells may have an increased sensitivity to heat [ref: 59] (they are at least as thermosensitive as oxygenated cells); cells with a low pH (less than 6.8) that are metabolically deprived (as in a tumor) are more heat sensitive; heat affects cells in S phase, which are known to be resistant to irradiation [ref: 349,385]; and blood flow in the tumor is reduced. [ref: 58,59,195] Heat causes a greater degree of mitotic delay than radiation, and this factor may affect the distribution of cells in the cell cycle after exposure to heat or radiation. [ref: 60,157] The sensitivity of hypoxic cells to heat is complicated by the possible association of low oxygen tension with nutrient deficiency or reduced pH. As Dewey and associates [ref: 59] pointed out, the response of the tumor may be affected by physiologic changes associated with lowering of the blood flow and oxygen tension produced by hyperthermia. The differential heat sensitivity of tumors is a consequence of tumor physiology, with nutrient deprivation [ref: 91,171,305] and lower pH [ref: 108] being the main contributing factors and not a consequence of the intrinsic state of malignancy of the cells. [ref: 111,112,121,194,273,283]

The biologic rationale for combining hyperthermia and irradiation in the treatment of cancer rests in two biologic mechanisms: radiosensitization and direct hyperthermia cytotoxicity. It can be hypothesized that hypoxic cells in the center of a tumor are relatively radioresistant but thermosensitive, whereas well-vascularized peripheral portions of the tumor are more sensitive to irradiation. [ref: 277,282] This supports the use of combined radiation and heat; hyperthermia is especially effective against centrally located hypoxic cells, and irradiation eliminates the tumor cells in the periphery of the tumor, where heat would be less effective. In experiments on a transplanted mammary carcinoma, Overgaard [ref: 274] reported no cures with 16 Gy (single dose), 22% with heat alone (43 degrees C, 60 minutes), and 77% when the two modalities with the same parameters were applied.

Biologic Aspects of Hyperthermia

Despite the publication of numerous observations of heat-induced alterations of subcellular structures and systems, [ref: 313] no consensus concerning the molecular mechanisms of cell kill has emerged. Most commonly postulated mechanisms involve damage to three major cellular structures:

Plasma membrane. Hyperthermia produces numerous alterations in the plasma membrane, including effects on membrane (e.g., receptor proteins and transport proteins), [ref: 31,180,206,304,362,407] extensive bleeding, [ref: 24,46] and regions of altered cholesterol content. [ref: 308] The involvement of damage to the plasma membrane in the lethal event is supported by the observation that membrane-active agents (local anesthetics) [ref: 435] and aliphatic alcohols [ref: 199] act synergistically with heat, and cell kill by the action of these agents alone is strikingly similar to the action of heat by itself. [ref: 200] In addition, several studies suggest a relationship between membrane lipid composition and cell kill. [ref: 117,143,176,177,250,435]

Cytoskeleton/cytosol. In tissue, culture cells contain stress fibers resulting from bundling of actin-containing microfilaments. Within 5 minutes of exposure of Chinese hamster ovary (CHO) cells to 45 degrees C, 90% of cells do not contain observable stress fibers. [ref: 109] Spindle microtubules are disorganized and disassociated (15 minutes) on exposure of CHO cells to 45 degrees C, [ref: 46] suggesting that this effect may be responsible for the increased thermal sensitivity of mitotic cells. The vimentin-containing intermediate filaments collapse on heat exposure to form a pernicular cap. [ref: 96,386,421] Most of the effects of heat on the cytoskeleton are reversible with postheat incubation at 37 degrees C. Hyperthermia induces alterations in both the structure and function of numerous cytoplasm elements: mitochondria, [ref: 421] lysosomes, [ref: 151,282] and protein synthesis apparatus. [ref: 137,224] Hyperthermia induces disruption of respiration and glycolysis, [ref: 36,68,233] which appears to be related to morphologic changes in mitochrondria. Polysomes are destroyed, [ref: 133,421] and protein synthesis is inhibited at the incubation step [ref: 75,137,284] and may be mediated by phosphorylation of initiation factors. [ref: 265] The association of polysomes and initiation factors with cytoskeletal structures is altered, [ref: 150] indicating the possibility of a functional correlate between heat-induced cytoskeletal changes and protein synthesis.

Nucleus. In addition to inducing a number of structural changes, hyperthermia alters or disrupts many nuclear functions. [ref: 313] One of the distinct substructures within the nucleus is the nucleolus, a heat-sensitive organelle, which undergoes marked changes at heat exposure that leave cytoplasmic organelles largely unaffected. [ref: 348] An increase in the overall median protein content is observed in nuclei isolated from cells exposed to hyperthermia. [ref: 315,387] The increased nuclear protein content is a large and rapid effect [ref: 315] and appears to result from the heat-induced association of specific proteins (including heat shock protein 70 [hsp70]) with the nuclear matrix [ref: 417] and the nucleus. [ref: 267] When cell kill, as a surviving fraction, is plotted as a function of excess nuclear protein content immediately after hyperthermia, a linear quadratic-type correlation curve is obtained, which holds even when cells are thermal-sensitized or thermal-protected by chemical modifiers. [ref: 337] When time of association between these proteins and the nucleus is included, the correlation becomes a simple exponential one (linear on the semilog plot) and applies for all conditions tested. [ref: 158] Additional studies implicate the association of excess proteins in the nucleus with inhibition of DNA replication [ref: 413,425] and DNA repair. [ref: 37,228,414] DNA replication is inhibited at all defined steps in the process: initiation, elongation, and assembly of replicated DNA into mature chromatin structure. However, these steps have different thermal sensitivities. [ref: 313]

A model for the mechanism of heat-induced cell kill based on the foregoing considerations proposed by a number of investigators [ref: 57,313,314,426] is as follows: disruption of critical plasma membrane structures (e.g., plasma membrane-cytoskeleton attachment points and protein channels); collapse of the cytoskeleton toward the nucleus; absorption of protein onto the nuclear matrix; disruption of nuclear functions, possibly involving inhibition of DNA supercoiling changes; and damage to critical nuclear structures.

When mechanisms of cell kill are considered, at least three modes of cell death can be identified. One mode of cell death involves apoptosis. The other two do not. One of these modes (to which the foregoing model applies) appears to occur after either at least one S-phase transit (not necessarily complete) [ref: 217] or at least one mitosis. [ref: 37] The other mode is rapid necrosis without cell-cycle progression. Part of the confusion regarding different mechanisms of cells arises because different workers were studying different modes of cell death without characterizing them. This situation is particularly telling when it is realized that different modes can occur for the same cell type. For example, L5178Y cells heated at 43 degrees C die by apoptosis, but when heated at 45 degrees C, they die by rapid necrosis. [ref: 218] Also, the cell death mode in CHO cells varies with the level of cell killing at the same temperature. [ref: 410] Regardless of the different modes, cell kill resulting from heat exposure can be represented typically as a surviving fraction plotted as a function of heating time (Fig. 24-1).



The resulting survival curves can be analyzed by either the target theory equation, S/So = 1 (1 - e**D/Do**n, or the linear-quadratic equation, S/So = e**alphaD betaD2. The former relationship has formed the basis of the current concept of thermal dose. [ref: 169]

Thermal Dose

The concept of thermal dose has arisen from attempts to convert heat exposures at various temperatures to equivalent time at a reference temperature (usually 43 degrees C) based on the biologic effectiveness of the actual temperature. [ref: 138] Sapareto and Dewey [ref: 324] developed a thermal dose concept that converts a thermal exposure to an equivalent exposure at an arbitrarily chosen reference temperature of 43 degrees C. This phenomenon has been observed in vitro and in vivo. [ref: 41,59,100,102,324]

These time-temperature conversions were shown by Dewhirst and associates [ref: 66] to be good prognostic indicators for spontaneous tumor treatment in dogs and cats when the thermal dose calculated for the coolest part of the treated tumor was used. These results indicated that equivalent minutes of exposure were the best predictor of long-term tumor response. However, Dewhirst and colleagues [ref: 67] stressed the importance of three-dimensional (3-D) dose mapping. A workshop on thermal dose demonstrated that a number of factors must still be evaluated and their importance resolved before this concept is generally accepted. These factors include the temperature of the transition or breakpoint, the R value below the breakpoint, the effect of step-down heating, the effect of thermotolerance, the effect of the interaction and radiation on cell survival, and the importance of blood flow and other physiologic factors. The workshop concluded that "any attempt to plan thermal treatments based on any of these dose concepts or to predict clinical response from a calculated dose is very inappropriate and premature." [ref: 322,323] However, Sapareto and Dewey's model is the most practical method available for the comparison of clinical treatments. Therefore, the method should be clinically tested to fully determine its potential usefulness.

Thermotolerance and Step-Down Heating

It has been frequently reported that mammalian cells are substantially more resistant to heat after prior heat exposure. [ref: 135] Henle and Leeper [ref: 136] noted that cells initially exposed to 45 degrees C became resistant to subsequent exposure to 45 degrees C if allowed a 10- to 20-hour period at 37 degrees C between treatments (Fig. 24-2).



Thermotolerance is a transient phenomenon and thus does not represent a selection of genetically resistant cells, which occurs at too low a frequency to account for this phenomenon. [ref: 131] The mechanism for thermotolerance is not known; however, protein or RNA synthesis must occur before thermotolerance can develop. [ref: 189,327]

Both Henle [ref: 134] and Li and associates [ref: 198] have indicated that prior exposure to temperatures above 43 degrees C sensitizes cells to lower temperatures. This phenomenon has been termed "step-down heating." Also, Li and colleagues [ref: 198] have shown that thermotolerance is inhibited for several hours immediately after exposure to 45 degrees C.

Studies indicate that thermotolerance is accompanied by enhanced ability to repair (restore) certain types of heat-induced cellular alterations. The following effects are repaired more rapidly in thermotolerant cells: nuclear localization of heat shock protein (hsp70), [ref: 267] disassembly of the cytoskeleton, [ref: 176] increased nuclear protein binding, [ref: 158] and inhibition of certain types of DNA repair. [ref: 431] Further studies may show that enhanced ability to repair heat-induced damage contributes more significantly to heat-resistance than does protection from damage.

Heat Shock Proteins

Thermotolerance appears to be closely related to the induction of a class of protein polypeptides of molecular weights of 25 to 110 kDa. [ref: 184,202,374] These heat shock proteins have been well characterized and occur as a result of gene transcription induced by thermal stress in Drosophila melanogaster [ref: 229] and most other living systems [ref: 337]; however, their function is unknown. A good correlation exists between the increased induction and degradation of these constitutive proteins and the induction and decay of thermotolerance (Fig. 24-3), whether induced by heat shock or other toxic stress phenomena. [ref: 203]



Particular interest has been generated by hsp70, [ref: 201] which migrates to the nucleus during heat shock. [ref: 267,420] Different types of thermotolerance appear to be associated with a period of enhanced synthesis of hsp70 and the period during which cells have elevated levels of hsp70. [ref: 185] Although it appears that increased levels of hsp70 are sufficient to cause increased heat resistance, it is becoming clear that they are not necessary. A series of heat-resistant cell lines from radiation-induced fibrosarcoma (RIF) tumors do not express increased levels of hsp70. [ref: 3] Also, transfection of cells with genes for hsp27 leads to increased heat resistance. [ref: 35] Although the cellular response to thermal stress appears to be one of the most conserved biologic mechanisms in nature, [ref: 337] the function of the various heat shock proteins remains by and large a mystery despite numerous eloquent studies.

Long-Duration Moderate Hyperthermia

It was long believed that chronic tolerance contraindicated treatment of tumors with moderate (41 to 42 degrees C) temperatures for long durations (i.e., more than 48 hours) with any effective cell killing. However, recent results have caused workers in the field to rethink this assertion. Mackey [ref: 215] found that, unlike CHO cells, which arrest in the G1 phase of the cell cycle and maintain chronic thermotolerance, HeLa cells progressed into S phase and were killed. Although there is debate regarding the role of cell-cycle progression, the fact that human tumor cells can be killed under these conditions has been confirmed by other groups. [ref: 9,303] The mode of cell death induced by this treatment is not apoptosis, but rather appears to be an alternative mode to those described earlier. [ref: 380] Thus, it appears that human tumors, where practical, might be treatable by this method. However, a word of caution should be advanced: some human colon carcinoma cell lines have been shown to survive and proliferate at 41.1 degrees C. [ref: 432] Thus, any clinical trial with moderate hyperthermia alone should include measurement of the thermal resistance of the tumor cells in question.

Heat Interaction with Radiation

Several good reviews are available on this subject. [ref: 59,65,275,375] The first and most generally observed phenomenon is that heat radiosensitizes cells. [ref: 59,326,363,364] Most reports note that the maximum increase in the slope of the radiation survival rate curves is 25% and that cells in S phase are more radiosensitized by heat than are cells in G1. [ref: 325]

The cause of this radiosensitization has not been firmly established; however, it is believed that the accumulation of proteins in the nucleus, which bind to the nuclear matrix after heat treatment, prevents the cell from repairing radiation damage. [ref: 37,228] The ability for enzymatic excision of radiation-induced thymine damage is inhibited in chromatin isolated from heated cells even when the repair enzymes are obtained from control cells, whereas the repair enzymes from heated cells were able to excise damage in chromatin from control
cells. [ref: 415] A correlation exists between the amount of excess nuclear protein and the inhibition of exogenous nucleases [ref: 416] and digestion of DNA in chromatin, which suggests that access to the DNA damage is blocked, thereby inhibiting repair. [ref: 159,416]

Another factor of possible clinical relevance is that cells in G1 are less sensitive to heat than are cells in S phase, whereas the opposite is true for cellular sensitivity to radiation (Fig. 24-4).




This effect often has been cited as one of the principal factors contributing to the "biologic rationale" for the clinical use of hyperthermia. In fact, a marked complementary synergism across the cell cycle was observed when heat (45 degrees C for 30 minutes) and radiation (4 Gy) were combined. [ref: 175] It can be argued that in a tumor the proliferating cells are likely be a small fraction of quiescent cells that are nutrient deprived [ref: 171] or at low pH [ref: 107] and are heat sensitive, and that the heat sensitivity is not affected by acute lypoxia. [ref: 106]

Enhanced cell kill by irradiation and heat has been defined as the thermal enhancement ratio (TER), expressed as follows:

Equation 1

The relationship of the TER in the tumor and the normal tissues is called the therapeutic gain fagtor (TGF):

TGF = TER in tumor/TER in normal tissue

Both TER and TGF should have values greater than 1 to have a positive therapeutic implication.

Urano and associates [ref: 395] and Stone [ref: 364] have reported a greater enhancement of early damage than late damage with a combination of irradiation and heat in mice.

Timing of Irradiateon and Heat Administration

A number of groups have considered how best to sequence heat and radiation. Dewey and co-workers [ref: 59] have hypothesized that if heat is delivered 3 hours before radiation, cells with a low pH will have minimal aoility to repair heat damage and therefore may be sensitized to the effects of subsequent radiation. Hill and Denekamp, [ref: 144] Field, [ref: 99] and Overgaard [ref: 276] strongly suggest that when preferential (selective) heating of the tumor exists in relation to normal tissues, it is best to administer the two modalities simultaneously. [ref: 47,87,167,173,237,279,281,312] However, when the temperature in the tumor and in the normal tissues is the same, some animal model studies suggest that the optimum therapeutic gain occurs when the heat is delivered 4 hours or more after exposure to radiation (Fig. 24-5).



These animal studies used tumor temperatures that may not be practical in humans. In human tumors treated with radiation and heat, the impact of timing of both modalities has varying influence on the effects of the treatment on the tumor or the normal tissues. [ref: 4,5,280]

The interaction between heat and radiation does not exhibit the same time-temperature relationship as does heat alone. This is proven by both in vitro and in vivo studies. [ref: 186,326] A maximum effectiveness is seen near 43 degrees C for simultaneous treatment, suggesting that there may be an optimal temperature for combined-modality treatment. However, when the modalities were given sequentially, little effect of temperature variations was found. [ref: 275] Mittal and co-workers [ref: 230] conducted experiments in transplanted RIF-1 fibrosarcomas in the flanks of C3H mice. Tumors were treated with fractionated x-rays (4 Gy twice weekly x 10) alone or in combination with heat (radiofrequency [RF] currents, 43 degrees C, twice weekly). Animals treated with irradiation alone or with heat and irradiation delivered with sequential fractionation (all heat sessions given before or after the radiation exposures) exhibited a 20% cure rate. In the animals treated with simultaneous combination of both modalities (heat delivered same day as irradiation, immediately after x-ray exposure), the cure rate was 70%. Another aspect of heat-induced radiosensitization comes from the long-duration moderate (41 to 42 degrees C) hyperthermia studies described earlier. Three separate groups [ref: 9,216,303] have shown that long-duration moderate hyperthermia produces thermal enhancement. Raaphorst and colleagues [ref: 303] applied long-duration moderate hyperthermia, combined with low dose-rate (LDR) irradiation, to produce thermal enhancement.

These considerations open the possibility of a wide variety of methods to combine heat and irradiation.

Interaction of Heat with Chemotherapeutic Agents

Hahn and associates [ref: 120,122] and other clinicians [ref: 139,262] have reported on the interaction of heat with a variety of cytotoxic agents. The type of drug, dose, temperature, and time of administration of the agents are important factors in determining cell kill by combination of these agents. [ref: 25,121,221] The interaction of heat and drugs in patients is not completely understood. Since Hahn's original work, [ref: 120] there have been numerous reports on this subject, and some excellent reviews have been published. [ref: 49,94,121]

Enhanced cytotoxicity of drugs at elevated temperatures is not a predictable process. The vinca alkaloids and most antimetabolites have only additive cytotoxicity with hyperthermia. [ref: 121,141] In two anticancer agents, AMSA and Ara-C, cell kill was actually inhibited at elevated temperatures [ref: 139] (B.E. Magum, personal communication). Doxorubicin (Adriamycin) and dactinomycin (actinomycin D) exhibit complex interactions with hyperthermia, and both increased killing and protection have been observed with these agents, depending on the scheduling of drugs and heat. [ref: 72,123]

A summary of interactions between anticancer drugs and hyperthermia is shown in Table 24-1. In addition, a category of agents not normally considered to be of therapeutic value at 37 degrees C shows significant killing ability at elevated temperatures. These agents include alcohols, amphotericin-B, cysteine, cysteamine, and AET (2-amino-ethyl-isothiourea).

The wide variety in mechanisms of drug cell kill precludes the idea that heat and drug interaction is a simple unilateral phenomenon. In fact, heat can enhance drug resistance in the case of doxorubicin [ref: 120] and dactinomycin. [ref: 72] As heating duration is increased, cells in culture become highly resistant to killing by either drug. This may be caused by heat-induced alteration in drug transport into the cell. [ref: 101]

The sensitizing effects of heat in combination with cisplatin have been confirmed in vivo. [ref: 73,262] Herman and co-workers [ref: 140,142] demonstrated in experimental models (murine RIF tumor) the substantial enhancement of antitumor effect obtained with the combination of radiation, heat, and cytotoxic agents (cisplatin). This hypothesis is being evaluated in prospective clinical trials. [ref: 141,142]


Physiologic Mechanisms in Hyperthermia

Microvasculature of Normal Tissue

There is great variation in the microcirculation of different tissues such as striated muscle, skin, and so on. Nevertheless, there is regularity in distribution within a specific tissue. [ref: 178] In a typical model, all exchanges between blood and parenchymal cells take place at the capillary level (microcirculation). True capillaries in normal tissues have a diameter close to that of an erythrocyte (7 to 10 micrometers).

Microvasculature of Tumors

At an early stage of tumor development, the tumor cells probably proliferate by using energy and nutrients supplied through the host's blood vessels. As the tumor grows, host vessels are occasionally incorporated into the tumor mass. As the demand for nutrients and oxygen exceeds the supply capacity of the host vessels, neovascularization in the tumor begins (formation of "buds" and, by confluence, "sprouts"). It has been suggested that certain humoral factors are important for the initiation of this process (e.g., tumor angiogenesis factor [TAF] and endothelial proliferating factor [EPF]). The capillaries formed by random fusion of sprouts are tortuous, elongated, and dilated, and they lack basement membranes. [ref: 80] A large proportion of tumor blood does not exchange with blood in the general circulation (stasis). This intermittent circulation – periods of stasis followed by resumption of blood flow -- is probably a normal feature of the intravascular transport system of neoplastic tissues. [ref: 118,404] The histologic patterns and functional status of vascular networks in malignant tumors vary, depending on the type, age, and size of the tumor. [ref: 404]

Tannock [ref: 383] suggested that the longer turnover time of endothelial cells (their slower proliferation relative to that of neoplastic cells) accounts for the decline in vascular density. Reduced vascular density together with the sluggish perfusion of blood through the capillaries may account for the decrease in total blood flow. [ref: 352,404] In general, tumor blood flow is vigorous in the periphery and sluggish in the center. [ref: 305,351]

Hyperthermia and Normal Tissue Microcirculation

Song and associates [ref: 353] observed that the blood flow of skin overlying the tumor and of muscle near the tumor is more than twice that of the skin and muscle far from the tumor. They attribute this phenomenon to inflammatory processes near the tumors. A significant increase in the blood flow occurred in skin and muscle both near and far from the tumor when heated to 43 degrees C for 1 hour. [ref: 350] It should be noted that the magnitude of increase was higher in the normal tissues adjacent to the tumor than in the tissues far from the tumor.

The dynamic changes of skin and muscle blood flow are both time dependent and temperature dependent. Peak blood flows are different for various times and temperatures; similar trends have been observed in muscle blood flow. Blood vessels in mouse gut were particularly sensitive to heat: a temperature of 41 degrees C for 1 hour to the lower body resulted in a sizable reduction in the visible venous tree. [ref: 95] The microcirculation of connective tissue was investigated in rats [ref: 61] and in rabbit ear chambers. [ref: 74]

Hyperthermia and Tumor Microcirculation

Several excellent reviews have been published on the subject of hyperthermia and tumor microcirculation. [ref: 81,91,305,370,405] The complex relationship between temperature, exposure time, and physiologic response for tumors and for normal tissue has been depicted in a simplified diagram in Fig. 24-6.



The data are based almost entirely on rodent studies (mostly murine models). Tumor vasculature seems to be less able to show vasodilation to elevated temperature and is more heat labile than the vasculature of normal tissue. Both tumor and normal tissues increase their blood flow as a result of hyperthermia exposure. However, the vasodilatory effect in normal tissue may be greater. Even in normal tissues, however, if the temperature exceeds 46 degrees C for a few minutes, vascular destruction occurs, and this leads to direct tissue damage due to ischemia. The temperature threshold for this type of vascular destruction in tumors (rodent models) is lower than in normal tissues (40 to 43.5 degrees C). [ref: 17,69,80,87,93,306,350,379,406,408] Confirmatory data for a similar effect in human tumors are yet to be provided. Song and associates [ref: 354] noted that vascular damage after hyperthermia is progressive even after the heating is completed. This damage makes the tissue highly sensitive to a second heat treatment given a few hours after the first. Extremely important information was provided by Reinhold and van den Berg-Block, [ref: 306] who studied the response of microcirculation to hyperthermia in five different tumors, growing in "sandwich" observation chambers in
the back of the rat. Their conclusions were as follows:

The various tumors required significantly different exposure times for inducing 50% stoppage of the tumor microcirculation (ST50). This seems to indicate that differences in the characteristics of the tumor cells were more important for causing microcirculatory stoppage than in the sensitivity of the cells of the blood vessels.

An increase in surface (volume) was observed in all four tumors examined; however, the rate of increase was significantly different among various tumors.

The relative velocity of the erythrocytes in selected capillaries in the tumors decreased as a result of hyperthermic treatment and was probably related to the tumor-specific ST50.

Several different mechanisms have been proposed to explain the vascular events occurring in tumors during hyperthermia (Fig. 24-7). [ref: 74]



However, none of the proposed single causative factors has been fully explained.

Hyperthermia and Intratumor pH

The pH of arterial blood is 7.4 and that of venous blood and interstitial fluid is 7.35. Intracellular pH usually ranges from 6.0 to 7.4 in different cells, averaging about 7.0. Studies show that no significant difference exists between the intracellular pH of normal cell lines and that of their malignant counterparts. [ref: 156]

Song and co-workers [ref: 353] and Bicher and associates [ref: 19] have shown that hyperthermia triggers an immediate and significant decrease in the pH of tumors. Bicher reported that when heating was terminated, the pH increased to 6.78 but decreased to 6.5 to 6.6 when the tumors were reheated.

Ryu and associates [ref: 317] observed that the lactic acid content in mouse tumors significantly increased with heating. Streffer and van Beuningen [ref: 370] also reported that hyperthermia caused an increase in the amount of both lactic acid and beta-hydroxybutyric acid in mouse tumors. The pH of human tumors is significantly lower than that of normal tissue [ref: 424]; there is no significant difference among different types of human tumors in this respect. [ref: 423] Also, human tumor pH appears to consistently increase after treatment with a combination of localized hyperthermia and radiation therapy. [ref: 401,423]