0006_EFFECTS OF HYPERTHERMIA ON NORMAL & TUMOR MICROENVIRONMENT 1 - 03.pdf

8/14/2019 0006_EFFECTS OF HYPERTHERMIA ON NORMAL & TUMOR MICROENVIRONMENT 1 - 03.pdf

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[Reprinted from RAI IOLO GY , Vol. 137, No. 2, Pages 523 530, Novem ber, 1980.]Copyright 1980 by the Rad iological Society of North America, Incorporated

E f f e c t s o f H y p e r th e r m i a o n N o r m a l a n d T u m o r M i c r o e n v i r o n m e n tHaim I . Bicher , M.D. , Ph.D. , Fred W . Hetze l , Ph .D. , Ta l ji t S . Sandhu, P h.D. , S tan ley Fr inak, B.S . ,Peter Vaup e l , M.D.,2 M i c h a e l D . O Ha r a , B . A . , M . S . , a n d T e r r e n c e O Br i e n , B . A .

The ef fec t s o f hyp er t herm i a o n pH , lo ca l b l oo d f lo w (L BF) and t i ssue o xyg en t en si o n (Tp O2)i n severa l no rm al and t um o r t issues were st ud i ed . I t was fo und t h at TpO 2, l o ca l b lo o d f lo wa n d p H a r e i n h o m o g e n e o u s i n t u m o r t is s u e . T p O 2 i s v e r y lo w i n c e r t a i n a r e a s w h i c h a l s os e e m d e p r i ve d o f b lo o d f lo w a n d a r e a t ve r y l o w p H . H y p e r t h e r m i a h a s a d u a l e f fe c t : a ttem pe ra tu res be low 4 1 C, i t inc rea ses b lood f low and Tp O 2 wh i le above 4 1 C, i t causes aco l l apse i n b l o od f l o w, l o wer TpO 2 and a sh i f t o f the t i ssue p H t o ward s ac i do si s fro m t h e a l -ready l o w pH va l ue s fo und i n t um o rs.INDEX TER MS: Blood, f low dynamics Hyperthermia OxygenRa di o l o g y 137:523-530, November 1980

T HE revival of interest in hyperthermia as a possibleadjunct to radiotherapy has led to increasing investi-gation of physiological alterations during the applicationof heat (2, 14, 16, 17, 19, 34, 40, 41 , 44, 45, 48). Studiesby both Eddy (16) and Reinhold et al. (33) employingchamber systems cite changes in the microvascularnetwork as a function of temperature and exposure time.The apparent sensitivity of the neovasculature was ob-served by both authors. A knowledge of the effect of hy-perthermia on tumor and normal tissue blood flow willenable us to un derstand its effects on hypoxic cells duringradiotherapy and to decide on the optimal amount of heatfor different neoplasms.

Studies with plethysmography show that elevation ofnormal tissue temperature to 41C is accompanied by aconsiderable increase in blood flow (28). Cater and Silver(10) recorded changes in tum or oxygen tension with hy-perthermia but not in temperature. They concluded thatdiathermy had not increased the oxygen tension in thetumor but, on the contrary, had decreased it.Bicher et al. (1, 3) reported that tumor blood flow in amouse leg tum or system increased up to 41C and thendecreased to 44C. The oxygen tension in the tumor, asmeasured with a platinum electrode, generally followedthe changes in tumor blood flow but the exact tumortemperature at which the oxygen tension decreased wasnot determined. Similar changes in b rain t issue oxygen-ation had been reported earlier by the sam e author (4).Although blood flow and the shifts induced in it by hy-perthermia in both tumor and normal tissue are important,there are other significant factors. Several s tudies indicatethat the pH of interstitial fluid in human and rodent solidtumors is 0.3 to 0.5 units lower than the normal tissue pHof about 7.4 (18, 26, 30, 31).Reduced pH has also been show n to affect the trans-

plantability of tum or cells heated in vitro (32). In a recentpaper, Gerweck (22) has shown that the inf luence of pHvaries with temperature and that there is a critical point inthe increased lethality of heat below pH 6.7. In addition,changes in glycolysis, respiration rate and lactic acidproduction will probably influence the response of thetissue.

Several other factors may change and subsequentlyinfluence the response of cells or tissues to supranormaltemperatures. Paramount among those are the vascularchanges, blood flow responses and the net result of thison tissue oxygenation that may change both the effect ofhyperthermia or radiation therapy when used in combi-nation in the treatment of tumors. Several authors havereported an increase of blood flow during hyperthermia.On the other hand, Dickson (15) has reported an increasein oxygen consum ption during elevated local temperatures.The net result, therefore, could be either an increase ordecrease in local oxygen tension.Englund et al. (20) and Sutton (46) have demonstratedthat during hyperthermia local blood flow increases in thetumor region and also in the organ hosting the tumor. W hilemeasuring the local oxygen levels as well as the localblood flow to the tumor, recent experiments demo nstratethat a net result of this process is an increase in the localoxygen tension. This increase is quite remarkable and alsoleads to abolishing the local autoregulation processes thatusually tend to keep oxygen levels constant in severalorgans as w ell as in tumors (1, 10, 11).This article will address itself specifically to changesin the microenvironment of normal and tumor tissue asmeasured directly w ith ultramicroelectrodes. The pa tternsof change of oxygen partial pressure, pH and microflowbetween tissue types, and the possible clinical implicationsare also discussed.

1 From the Department of Therapeutic Radiology, Division of Radiation Biology and Physics, Henry Ford Hospital, Detroit, MI 48202. Submittedfor publication 5 April 1980; accepted after revision 12 August 1980.Supported in part by Grant CA25780-01 from the National Cancer Institute, DHEW .2 Department of Physiology, University of Mainz, Saarstrasse 21, D-6500, Mainz, West Germany. shan

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524 HAIM I. BICHER AND OTHERS November 1980

E F F E C T O F HYPERTHERMIA ON TpO2100-

TpO2 _mmHgo_45-TempC

2 5 =Fig. 1. Effect of microwave hyperthermia on TpO 2 in a representative mouse tumor. The upper channel records TpO2 and the lower chann eltemperature in degrees Celsius. Microwaves are on when indicated by the timing pulse. One minute is indicated by the space between two largepeaks on the microwave tracing (center). Cooling and declining pO2 can be seen when the microwa ves are turned off.

MATERIALS AND METHODS1: Tissue Systems

Measurements were performed in both mouse andhuman tumors as well as in two normal tissues as fol-lows:a) C3H mouse mammary adenocarcinoma: In situstudies were carried out in fourth generation transplantsof C3H mam mary adenocarcinoma implanted in the hindleg of C3H SED-BH mice. The tumors were obtained fromthe Rad iobiology D ivision, Massachusetts Gene ral Hospital(43). This is a syngenetic implantable tumor that is kept atour facility using solid tissue transplants inoculated su b-cutaneously into recipient mice. Tumors used for experi-mentation were approximately 10 mm in diameter. Themice were an esthetized during microelectrode introductionwith a combination of ketamine 40/~g/kg i.m. and Tho-razine, 50 mg/kg i.m.

b) Human tumors: Determinations were made insubcutaneous me tastases in a g roup of 15 p atients. Tu-mors represented different histologies and locations, butare grouped together as the responses were homoge-neous. There were four melanomas, six chest wall re-currences of mammary adenocarcinoma and five pe-ripheral metastases of squamous cell carcinoma of thelung. The patients were not anesthetized. Oxygen wasadministered through a facial mask when required (seebelow: Oxygen Ultramicroelectrodes).

2. Normal Tissuesa) C3Hmouse muscle: Employing the same animalsystem as in l a) measurem ents were made in the muscletissue of the hind leg. Determinations were obtained in bothcontrols and in animals bearing an implanted tum or in the

opposite leg. Since no difference was observed, no dis-tinction is made in the results.b) Cat brain: All brain studies were performed incats. In each case the animal was anesthetized withNembutal (30 mg/kg) prior to and during the procedure.After opening the scalp, a small opening (5 mm) is made

in the skull with a dental hand drill and the dura is carefullyopened. Throughout the entire procedure, including themicroelectrode introduction and measurements, theopening is kept m oist with isotonic saline.

3. Physiological Determinationsa) Oxygen ultramicroelectrodes: The 02 ultrami-croelectrodes were gold-in-glass types as described byCater and colleagues (12). They were mad e by pull ing aglass tube (KG-33, ID 1.5mm, OD 2.0mm, Garner Glass

Co., Claremont, California), encasing a 20# gold wire(Sigmund Cohn Co rp., Mt. Vernon, New York) in a DavidKopf Mo del 700C vertical pipette puller. The exposed goldtip is about 10# in diameter, and coated with a Rhoplex(Rhom H aas, Philadelphia, Pennsylvania) membrane aspreviously described (4). This probe is used as an externalreference 02 microelectrode.The operative characteristics of 02 microelectrodes insolutions have been well defined prior to their use formeasuring in vivo tissue responses, their more commonpresent application (5, 39).Their performance has proven to be in good agreementwith what could be expected a ccording to the theories ofpolarographic recording of partial pressures of oxygen intissue. The adoption of industrial technology ensu res goodreproducibility between different electrodes, and differentelectrodes in different experiments, and m akes a hithertocomplicated and sophisticated technique into a simpledetermination, potentially useful in a variety of physio-logical and in vitro experiments.The electromagnetic force to activate the oxygencathode and its current output are provided and measuredwith a Transidyne Model 1210 microsensor amplifier(Transidyne General Corp., Ann Arbor, Michigan) and re-corded with an appropriate chart recorder.Electrodes are calibrated as described by Silver (38) inbuffered saline solutions of known p O2 values. The e lec-trodes are conditioned by placing them in buffered salineand applying 0.8 V potential for 2 hrs. After this treatmentthey are usually very stable. The current reading at zero


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R a d i a t i o nVol. 137 EFFECTS OF HYPERTHERMIA ON NORMAL AND TUMOR MICROENVIRONMENT 525 Biology

T p O 2 IN MOUSE TUMOR46 MICROWAVE HYPERTHERMIA

TpO2(mmHg)~5 0

- ~0

J 250

Fig. 2. In this figure, microwaves (MW ) are indicated by the solid center line. Note that the temperature~s constant at 46C except for the first 5 minutes. The drop in TpO2 is clear after only 10 minutes at46C.

oxygen tension is very low (residual current) and the re-sponse of the microelectrode to changes of oxygen tensionis very rapid.The current voltage polarogram of these electrodesshows a quasi-plateau between 0.3 and 0.7 V. The plateau,

however, is not absolute and small differences can bedetected at the extreme values. This type of plateau canbe expected when using open tip electrodes [Daviesand Brink (13)]. In these experiments a polarizing voltageof 0.6 V has been used. The relationship between currentoutput and oxygen tension is linear, the current per mm Hgbeing of the order of magnitude of 0.6 X 10-11A.In human e xperiments, a platinum-iridium Teflon-coatedwire, 120# in diameter, was used as the 02 electrode.Although the calibration was no t as reliable for determiningactual TpO2 values, it was found in determ ining transients(response to oxygen breathing or hyperthermia) that thevalues correlated well with those obtained using micro-electrodes. The responses to 02 breathing were deter-mined by administering pure oxygen to the mouse or pa-tient for one minute. The height of the tissue oxygen re-sponse provided an indication of the ability of the circu-lation to transport oxygen, probably dependent on the bloodflow. The temperature artifact of both types of oxygenelectrodes was determined and found to be 5 % per degreeCelsius. All results were corrected b y taking this artifactinto account.b) Other microelectrodes are now available tomeasure K+, CI-, pH, etc. An antimony electrode has longbeen used in the measurement of pH, but investigatorshave found that the electrode potential is linear with in-creasing pH only to pH 7.0. Consequently, these elec-trodes require frequent calibration. Bicher and Ohki (6)

successfully used an antimony pH microelectrode. Basi-cally, it consists of a very finely drawn (1 micron or lesstip diameter) glass micropipette which has a thin filmovercoating of antimony. It is then coated with two layersof insulating epoxy resin leaving an exposed tip approxi-mately 2 microns in length. A microcalomel electrode in-serted into the same cell, tissue or solution serves as areference. Results obtained in the giant squid axon werevery satisfactory (6).

Designs for glass pH microelectrodes have been de-veloped, most notably by Hinke (27) and Thomas (47). TheThomas electrode consists of a Pyrex glass micropipettedrawn to a fine point into which is inserted and fused asecond pipette m ade of pH-sens itive glass. The tip of thepH-sensitive glass pipette is recessed in the tip of thePyrex glass pipette and the electrode is filled with KCIelectrolyte. The Hinke-type electrode also consists of apH-sensitive glass micropipette inside a Pyrex glass pi-pette, the major difference being that the tip of the pH-sensitive micropipette is not recessed but extruded fromthe Pyrex glass p ipette. A silver/silver chloride electrodeis inserted into the electrode stem w hich is filled with 0.1N HC I. The Hinke microelectrode then, has an exposed tipand its response time is instantaneous . This is an advan-tage over the Thomas microelectrode in which the re-cessed tip may result in a response time of up to severalminutes.c) Microflow: Flow in microareas of tumor tissuewas determined using the hydrogen diffusion m ethod asdescribed by Stosseck et aL (42). The method is based onthe polarographic determination of the amount of hydroge ngas reaching a platinum electrode (hydrogen detector) froma hydrogen-generating electrode located at a fixed dis-


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52 6 HAIM I. BICHER AND OTHERS November 1980

60-

m 15-10-5-0-

BRAIN T ISSUE pO 2 vs.B R A I N T IS S U E T E M P E R A T U R E

temP. effect on microelectrode (52%/C)

3~5 36 37 3~ ~9 4~0 41 4~2 ~3 4~4 4~5Tem perature (C)Fig. 3. Brain tissue pO2 (equ ilibrium, steady state values) is plotted as a function of brain tissue tem-perature in this composite figure obtained in a representative rabbit brain. A breaking p oint is clearly seenat approximately 43C. The temperature artifact induced in the microelectrode (5.2 %/C) is plotted onthis graph to clearly show that the observed curve is not artifactual in nature.

tance. The amount of hydrogen reaching the readingelectrode de pends on the generation and diffusion rates,which are constant, and the blood flow clearance of hy-drogen which can be thus determined. In the present ex-periments, two platinum in Teflon 100# wires placed 100#apart were used. The reading device was applied to thesurface of the tumor. In the present experiments onlyrelative changes in the rate of blood flow were determined.This method was used in the experiments on mouse tu-mors in situ [Methods la].d) Temperature determinations: Tumor and mousecore temperatures were recorded with Copper-Constantanmicrothermoco uples (tip diameter 30-100/~) inserted intothe tumoral tissue in close proximity to the 02 micro-electrode or in the animals rectum for core measure-ments. An Om ega Engineering Model 250 Digital Voltmeteramplifier was used as a link between the microthermo-couple and the polygraph. Microwaves of a frequency 2450MHz w ere produced by a Raytheon M agnetron and deliv-ered through a specially designed 2.5-cm side square TEl0waveguide applicator loaded with low-loss dielectric ma-terial with a dielectric constant of 6 (36).

RESULTSAs seen for a representative mouse tum or in Figure 1,there is a rise in TpO2 that parallels the application of the

microwaves and closely follows changes in tissue tem-perature. The respons e is very fast, with TpO2 increasingshortly after the rise in temperature, and then decreasingas the tumor cools off. This effect was always present

when heating was ca rried out up to 41C. At higher tem-perature (Fig. 2), there was an initial increase in TpO2which was followed by a decrease to very low levels asthe temperature was held constant at 46C.Similar effects are also seen in both normal tissuesstudied (mus cle and brain) with one major difference, thisbeing the tempe rature at which the TpO 2 begins to fall orthe breaking point. In Figure 3, the rise in oxygen tensionin brain continues up to 43C but declines sha rply at highertemperatures. A com posite of representative results ob-tained for both normal and tumor tissues is presented inFigure 4. It is evident that the breaking point (in the pO2 vstemperature cu rve) exists for each tissue, and at least forthe tissues studied in these experime nts (at least 15 de-terminations per tissue type), the breaking point temper-ature is significantly lower for tumor.Figures 5 and 6 sh ow exam ples of the effect of hyper-thermia (low and complete range hyperthermia, respec-tively) on local blood flow in mo use tum ors. In both casesit is clear that blood flow increased significantly up to ap-proximately 41 C. In a ddition, examination o f the data inFigure 6 shows the strong correlation between decreasesin TpO2 and blood flow as the temperature is increased upto 45C.In 8 different animals with implanted tumors, a largenumber of single-point pH determinations were made bothprior to and following hyperthermia. The results are plottedin histogram form showing frequency of values at differentpH levels (Fig. 7). This method of representing microen-vironment tissue distribution was introduced by Stossecket al. (42) for 02 tissue levels.


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R a d i a t i o nVol. 137 EFFECTS OF HYPERTHERMIA ON NORMAL AND TUMOR MICROENVIRONMENT 527 Biology

Brain

,,, .. ~Mu scleT u m o . r . . . . . ./

3 8 3 9 4 0 4 1 4 2 4 3 4 4 4 5 4 6T e m p e r a t u r e (C)

Fig. 4. Relative tissue pO2 plotted as a function of temperaturesimilar to the plot in Figure 3. In this case representative curves obtainedfor tumor, brain and muscle are superimposed so that the differentialeffect and the different position of the b reaking point can be seen moreclearly. Note that relative TpO2 has b een used to aid in clarification.

The mean value of tissue pH was found to be 6.8 pHunits in mouse tum ors. Upon h eating for one hour a t 43C,there was a pH decrease of 0.5 to 1 pH u nit to an averageof 6.2. The individua l variations from point to point withina single tumor are seen m ore clearly in Figure 8. For eachvalue of pH o btained at normal temperatures, the pH mi-croelectrode was left in place throughout the one hour of43 hyperthermia and a new value ob tained. In each case,related data points are joined by a solid line.Breathing pure 02 for one minute usua lly caused a verysmall rise in TpO2 indicative of the autoregulation of themicrocirculation. Local hyperthermia caused an increasein this response proportional to the local tumor tissuetemperature. The threshold was about 37.5C and a 40-50mm Hg increase could be recorde d at approximately 41C(Fig. 9).The effect was reversed when the tumor w as heated to45C (for exam ple, see Fig. 6).

PH EFLOW ~ ......

MW 50TEMP 40I2O

t rainFig. 5. In this graph, the effect of low-level microwave h yperthermiaon pH and blood flow on a mouse tumor is shown. The upper tracingindicates a decline in pH values as hyperthermia is continued, eventhough the tem perature neve r reaches 40C. The effect on blood flowis shown in the second tracing with an increase in flow being in the downdirection. The dramatic increase in blood flow required a recalibrationafter 5 minutes wh ich is the reason for the vertical shift in the curve atthat point.

DISCUSSIONThere is considerable controversy as to whether theblood perfusion of tumors is greater than that of normaltissues. LeVeen et al. (29) state that tumor blood flow, asmeasured by an isotope dilution technique from su rgicallyexcised material, was 2%-15% of surgically excisednormal material. They claim that the success of RF energy,in hyperthermia, is due to differential cooling of the norm al

tissue by the improved normal tissue perfusion. Usingtransplanted tumors in rats ovaries or kidneys, Gullino andGrantham (25) showed that the tumor blood flow per mil-ligram of tissue was 10-20 time s less than the blood flowper milligram of tissue of the host ovary or kidney. How-ever, it must be pointed out that in this experiment, thetumor was 10-100 times greater in weight than the hostovary or kidney and the actual total perfusion to the isolatedovary or kidney increased following the growth oftumor.

50

40

~o

o o20 22 24 26 28 30 32 34 36 38 40 42 44

100

TEMPERATURE CFig. 6. Mouse tumor blood flow and tissue oxygen tension plotted as a function of temper-ature. All readings were taken in the same se ries of animals. Steady state values obtained forblood flow (Iq) and TpO2 (I) in this series are plotted. It is clear that a strong correlation existsbetween change in blood flow with temperature and the change in tissue oxygen tension withtemperature.


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30- C3H MOUSE MAMMARY CARCINOMA (N=8)~ normothermia (n=96).... after 1 hour of 43C hyperthermia (n=108)

o~ 20t

II

r- -i

I6:0 614 6 8

tissue pHFig. 7. Histogram of tissue pH levels obtained in mouse tumor. Atotal of 96 determinations were mad e at normal temperature, while 108were made following one hour of 43C microwave hyperthermia. Themean value of pH o btained in the control group was approximately 6.75,while in the group after one hour of hyperthermia the mean value wasapproximately 6.2.

By using radioactive microspheres in very large humantumors, Shibata and Maclean (37) showed microspherenormal tissue-to-tumor distribution ratios ranging from 3-1to 20-1. Bierman et al. (7) vi a differential between ar-terial and venou s blood pO2 as an index of blood flow in12 patients with metastatic, neoplastic lesions showed thatthere was a greater increase in blood flow through thetumors than in comparable normal tissue, possibly due tothe presence of arteriovenous shunts. Bierman et al. (8)also noted an increas e in the thermal index of supe rficialtumors, as compa red with the normal tissue.The studies reported here clearly demo nstrate that lo-calized microwave hyperthermia causes a rise in bothblood flow and TpO2 up to some temperature with a fallat higher temperatures. It also appears that the tempera-ture at which the breaking point occurs is characteristicof the specific tissue. The m echanism o f this effect seemsto be predominantly mediated through the blood flowchange s, any metabolic effects being secondary to a mi-crocirculation that is activated at m oderated hyperthermictemperatures and dam aged at higher ranges. These resultsalso indicate that the normal tissue microcirculation isbetter able to cope with hyperthermic stress.The rise in tumor temperature up to 41C leads to asignificant increase in tumo r blood flow (TBF). This effecthas also been demonstrated by Englund et al. (20) andSutton (46) for both the tumor region and host organ. Asto the cause of this increased flow, presumably differentfactors including systemic and local autoregulation haveto be taken into accoun t. The oxygen pa rtial pressures inseveral subcutaneous tumors in animals and in humans

7.0

6.5~

tissue pH

6.0~

5.5 ,normothermia after hr of43C hyperthermiaFig. 8. This figure shows changes in pH induced by one hour of43C hyperthermia, exam ining single points within a single tumor. Ineach case a read ing was taken with the pH microelectrode which wassubseq uently left in place throughout the period of hyperthermia, fol-lowing which a second pH reading was obtained. It is clear that in eachcase the pH fell, the most dramatic being a drop of almost one completeunit of pH.

as me asured with 100/zm tip f loating 02 electrodes fol-lowed the change in blood f low (2).A further rise in tissue tem perature up to 42C resu ltsin a marked breakdown of tumor blood f low to somewhatbelow the initial value. Similar results are obtaine d for insitu tumors, both in humans and mice. In metastatic lesionsinvolving the skin, increases in flow occur due to elevationsof temperature up to 40C. With tumor temperature ele-vated to 4 6C, the tissue oxygen tension in microareas ofthe tumor decreases following a drop in tumor blood flow.This correlates with the studies of Reinhold and Be rg-Blok(35), who found that at 42C, the center of a sandw ichtumor becomes necrotic due to a decrease o f tumor mi-crocirculation at this temp erature. These resu lts, however,do not correspond with Songs finding that hyperthermiaat 43C does not change circulation in tumors, but in-creases it in normal tissues (40).The restriction in blood flow at 42C and the increasein total vascular resistance, respectively, presumably resultfrom a series of factors. As main determ inants of the de-cline of blood flow, a reduction of red cell deformability,multiple microthrombi as well as occlusions of micro-vessels have to be taken into account.Reduced pH in tumors as compared to normal tissueshas been repo rted by several authors (18, 26, 30, 31). Thereduced pH of tumor f luid may be du e in part to elevatedlactic acid production resulting from poor tum or vascularity


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RadiationVol. 137 EFFECTS OF HYPERTHERMIA ON NORMAL AND TUMOR MICROENVlRONMENT 529 Biology

and reduced oxygen tension. Reports also indicate thattumor cells produce lactic acid at an elevated rate evenunder oxygenated conditions (49). The significance oflowered pH on hyperthermia cell kil ling has been clearlydemonstrated by Gerweck et al. and several other authors(22, 24, 32, 48 ). Cell killing is increased by factors of 5 andabove w hen chron ically hypoxic cells are heated to 42Cat a pH only 0.5 unit below norma l.The result of a pH drop in cancer tissue during or fol-lowing hyperthermia is no t surprising if one considers thefamiliar principle that temp erature strongly influences thebuffering processes and hence the pH. There is usually ashift to lower pH values if the temperature is elevated.Qualitatively, these changes are quite similar to thoseobserved in blood. In addition, the increase in the CO2partial pressure during hyperthermia induced by changesin cellular metabolic pathways enhances tumor tissueacidosis. These factors, coupled with the observedbreaking point in blood flow which would carry away me-tabolites, may provide a distinct therapeutic advantage forthis mod ality.

From the given data, a series of consequences resultsfor this temperature range of maximum tumor blood flow.As the oxygen partial pressures in malignant tumorsgenerally follow changes in blood flow, it can be expectedthat the radiosensitivity of cancer tissue may be improvedduring increased blood flow, thus producing a significantprolongation of survival time of tumor-bearing animals ifthey are treated with local hyperthermia in combinationwith irradiation. The clinical utility of the simultaneouscombination of short-term, moderate tumor hyperthermia(41C) and irradiation is cu rrently being exam ined in vivoin our laboratory.A second and perhaps more obvious conclusion can bederived from the data. It appears that the breaking pointin blood flow (the temperature at which blood flow beginsto decrease) in tumors is lower than in some normaltissues. Heating a region of the body which includes bothtumor and no rmal tissues to a temperature which is abovethe breaking point for the tumor but only ap proaching thatof the normal tissue would continue perfusion at levelseven above normal while blood flow to the tumor would bereduced. With the increased metabolic activity and de-creased flow, drama tic shifts in pH such as reported herewould occur. As previously described by Gerweck andothers (22-24), the combination of reduced pH and in-creased temperature is extremely cytotoxic. This effectalone should eradicate large areas of the tumo r, includingthe radioresistant hypoxic areas, prior to the start of anycombination with irradiation.W e may conclude from the results presented here thatthe therapeutic effectiveness of hyperthermia may result,at least partially, from several induced physiologicalmodifications. First, moderate (41C) hyperthermia incombination with ionizing radiation m ay result in improvedtumor response by increasing oxygenation and hence,radiosensitivity coupled with a decrease in tumor pH.Second, higher levels of hyperthermia, 42C and above,

TI302 RISE INDUCED BY MICROWAVEHYPERTHERMIA EFFECT ON 02 BREATHING

HUMAN TUMORS

control

TpO2

o50TpO2 RISE INDUCED BY MICROWAVE HYPERTHERMIAEFFECT ON 02 BREATHING - MOUSE TUMORS

29

control 5o

~ 1 min.

TpO2(mmHg)~o~ 150

~ 15

Fig. 9. Effect of microwave hyperthermia on tissue pO2 responseto oxygen breathing. In all cases the oxygen microelectrode was inplace within the tumor. Under both norma l and elevated temperaturesthe subject was given pure oxygen to breathe for a period of one m inuteand the resultant pO2 p rofile in tissue determ ined.a. In a representative human tumor, the normal (control) pO2 re-sponse is seen on the left, while the response differences in temper-atures up to 4 0C are see n in the pan el to the right.b. In a mouse tumor, the resting temperature is significantly lowerdue to position of the tumor in the limb. The trend in pO2 responseprofiles is similar to that seen in human tum ors, the maximum resp onsebeing obtained at 41C.

may be directly tumoricidal because of elimination of tumormicro-blood flow and a concomitant sharp reduction intumor pH while normal tissue can still be properly per-fused.

REFERENCES1. Bicher HI, Hetzel FW, DAgostino L: Changes in tumor tissueoxygenation induced by microwave hype rthermia. Int J RadiatOncol Biol Phys 2:157, Oct 19772. Bicher HI, Mtagvaria N, Hetzel FW: Changes in tumor tissueoxygenation induced by microwave hyperthermia. Ann NY AcadScience (in press)3. Bicher HI: [In] Proceedings of the 2nd RTOG HyperthermiaMeeting, Chicago, II1., Nov 28-29, 19774. Bicher HI: Increase in brain tissue oxygen availability inducedby localized microwave hyperthermia. (In) Silver I, Erecinska

9a

9b


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M, Bicher HI, eds: Oxygen Transport to Tissue. New York, Ple-num Press, Vol Ill, 1978, pp 347-353

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Haim I. Bicher, M.D., Ph.D.Therapeutic RadiologyE & R Building, Room 3056Henry Ford Hospital2799 We st Grand Blvd.Detroit, MI 48202

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