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[Reprinted from RADIOL OGY Vol. 137 No. 2 Pages 511 513 November 1980.]Copyright 1980 by the Radiological Society of North Am erica Incorporated
T h e P h y s i o lo g i c a l f fe c t s o f H y p e r th e r m i a l
Haim I. Bicher M.D. Ph .D.
In the appl icat ion of hype rtherm ia to control can cer physiological factors such as pH p02and blood flow must be docum ented n v vo a t norma l a nd e l e va te d te mpe ra ture s for boththe tumor and i ts normal host t issue. The present symposium was arranged to gather recent
resea rch d one in this area and to expose the problem s inherent in the se ef forts .
INDEX TERM S: Blood, flow dynamics Hyperthermia Oxygen
Radiology 137:511-513, Novem ber 1980
H YPER THERM IA is currently being emp loyed in clinical
t r ials to control cancer. The protocols in these tr ialsemploy hypertherm ia either as the only treatment modali ty
or in combination with other acce pted m odali ties such asradiat ion therapy and chemotherapy.
The current interest in hypertherm ia is prompted m ainly
by some very interesting radiobiological observationsmade at the cellular level. In vitro studies (1-4) demon-strate that heat-induced lethal dama ge to cells in culturefollows a quasithresh old exp onential response sim ilar inshape to cell survival curves obtained for ionizing radiationexposure or treatment with some cytotoxic agents. Dif-
ferent ce ll lines exh ibit widely different therm al sensitivities
2, 3). Heat survival curves at 45.5°C for aerobic and hy-poxic cel ls using CH O cel ls show that hypoxic cel ls aremore heat sensitive than well oxygenated cells (5). Similarobservations were m ade by Schulman and Hall (6) for V79Chinese hamster cells and by Kim etaL (7) for HeLa ce lls.Assuming that the W138VA 13/2 RA cells model the
malignant cells of a human tumor and Wl38 cells model
culture (18, 19) it was observed that there is an increasein Do of a subsequent hyperthermia survival curve. Ther-motolerance is induced during a 3-5 hour incubation pe riod
at near p hysiological temperatures after heating for a shorttime at temperatures greater than 43°C (20, 2t).
In vitro studies (7, 10, 22, 23) also have demonstrated
that hype rthermia combined with ionizing radiat ion has asynergistic cell killing effect. The importance of the se-
quence in which he at and radiat ion are applied has bee nstudied in detai l by Sapareto et al (22). The synergist iceffect is most pronounced for radioresistant S-phase ce lls
(22, 24). There are no in vitro data indicating differentialsensitization of cancer cel ls as opposed to norm al tissuecells.
In the recent literature (26-38), several investigators
have achieved local tumor control using hyperthermia
either alone or in combination with irradiation. Crile 26)studied the effectiveness of hyperthermia and the de-
pendence of cure on the temperature achieved and the
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51 2 HAIM I. BICHER November1980
when combining hyperthermia and irradiation. The in vitro
results indicate that, with heating time adjusted to achievethe same ki ll ing from he at alone at various temp eratures,
a decrease in temperature increases the relative killing
from the interaction of radiat ion and he at. This is in con-tradiction to the in vivo results (25) which indicate that theopposite should occur.
In order to ful ly make u se of in vitro observations madeunder controlled conditions in the application of hyper-
therm ia to cancer control, the ph ysiological factors such
as pH, oxygen consumption, nutrients, and blood flow ofboth tumor and normal host tissue should be measured in
vivo Furthermore, these factors should be documentednot only at normal temperatures but also under hyper-
thermic conditions. Under certain conditions a selectivedestruction of tumor tissue m ight be possible with norma l
tissue sparing. For example, several studies (39-42) in-
dicate that pH of fluid in human and rodent solid tumors is
lower than the normal tissue pH of 7.4. Paramount am ongthe other factors which may change and subsequently
influence th e respon se of cel ls or tissues to supranorm al
temperatures are the vascular changes, blood flow re-
sponse and the ne t result of this on tissue oxyg enation. Thelast factor may chang e the effect of both hypertherm ia andradiation therapy when used in combination. Insufficient
information is available on the temp erature m odificationsof tumor blood supply, tumor oxygen tension and con-
sumption and respiratory gas exchang e by malignant cel lsin vivo
This symposium on the physiological effects of hyper-thermia was arranged in order to assemble recent researchon the physiological response of normal and tumor tissue
to hyperthermia.
cells by hyperthermia (letter). Br J Radiol 48.’872-874, Oct
19758. Kase K, Hahn GM: Differential heat response of normal and
transformed human cells in tissue culture. Nature 25,~:228-230,15 May 1975
9. Bronk VV: The rmal potentiation of mamm alian cell kil ling. Cluesfor understanding and p otential for tumor the rapy. (In) Lett JT,Adler H, Felle M, eds: Advances in Radiation Biology. New
York, Academic Press, Vol VI, 1976, pp 267-32310. Thrall DE, Gerwe ck LE, Gillette EL, et al: Response s of cells in
vitro and tissues in vivo to hyperth ermia and x -irradiation. (In)Lett JT, Adler H, Felle M, eds: Advances in Radiation Biology.
New York, Academic Press, Vol. VI, 1976, pp 211-227
11. Har-Kedar I , B leehen NM: Exp er imental and cl in ical aspects ofhyperthermia applied to the treatment of cancer with special
reference to the role of ultrasonic and microwave he ating. (In)Lett JT, Adler H, Felle M, eds: Advances in Radiation Biology.New Y ork, Academic Press, Vol VI, 1976, pp 228-266
12. Palzer R J, He idelberger C: Influence of drug s and synchrony onthe hype rthermic kil ling of HeL a cells. Cancer Res 33=422-427,Feb 1973
13. Chen TT, He idelberger C: Quantitative studies on the m alignanttransformation of mouse prostate cells by carcinogenic hydro-carbons in vitro. Int J Cancer 4:166 -178, 15 Mar 1969
14. Kim SH, Kim JH, Hahn EW: The enhanced killing of irradiated
HeL a cells in synchronous culture by hyperthermia. Radiat Res66:337-345, May 1976
15. Gerweck LE, Rottinger E: Enhancement of mammalian cell
sensitivity to hyperthermia by pH alteration. Radiat Res 67:
508-511, Sep 197616. Gerweck LE: Modification of cell lethality at elevated tempera-
tures. The pH effect. Radiat Res 71).’224-235, Apr 197717. Hahn GM: Metabolic aspects of the role of hyperthermia in
mammalian cell inactivation and their possible relevance to
cancer treatment. Cancer Res 34. 3117-3123, Nov 197418. Gerner EW, Schneider M J: Induced thermal resistance in HeLa
cells. Nature 256:500-502, 7 Aug 1975
19. Hen le K J, Leepe r DB: Interaction of hyperthermia and radiationin CHO cells: recovery kinetics. Radiat Res 66;505-518, Jun
197620. Harisiadis L, Sung DI, Hall E J: Thermal tolerance and re pair of
thermal dam age by cultured cells. Radiology 123.’505-509, May
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R a d i a t i o n
PHYSIOLOGICAL EFFECTS OF HYPERTHERMIA 513 BiologyVol. 137
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