The response of mouse skin to combined hyperthermia and X-rays.

The effects of combined hyperthermia and X-irradiation were studied in the skin of the mouse ear. Ears were heated for 1 hour by immersion in a waterbath at temperatures ranging from 37 degrees C--43 degrees C. These heat treatments had little visible effect alone, but when combined with X-rays, enhanced the radiation response. Enhancement depended on the degree of heating. When heat was given immediately after X-rays, the radiation dose to cause a given skin reaction had to be reduced by about 10 per cent for 37 degrees C and about 40 per cent of 43 degrees C. The timing and sequence of the two treatments were important. Heat after X-rays was less effective than heat before X-rays. When heat followed X-rays, the enhancing effect was lost completely if the interval exceeded 4 hours. When heat preceded X-rays, the effect was lost more slowly, depending on temperature. The implications of this for the treatment of cancer by combined therapy are discussed.     

Hyperthermia in combination with oxidative stress induces autophagic cell death in HT-29 colon cancer cells

The purpose of this study was to evaluate the mechanism of ROS-induced hyperthermic cell death in a colon cancer cell line. HT-29 colon cancer cells were exposed to heat (43 degrees C) in the presence of tert-butyl hydroperoxide (t-BOOH). t-BOOH combined with hyperthermia significantly decreased cell viability as compared with t-BOOH or hyperthermia alone. This decrease in cell numbers was associated with retardation in the S phase transit and not through apoptosis. Cell death was noted to be accompanied by specific features characteristic of autophagy: the presence of cytoplasmic autophagic vacuoles; autophagosome membrane association of microtubule-associated protein light chain 3; accumulation of acidic vesicular organelles; and increased incorporation of MDC in the autophagosome. Thermal sensitization through modulation of cellular ROS may represent a novel approach to increase the efficacy of hyperthermia as an anticancer modality.     

The effect of hyperthermia on radiation-induced carcinogenesis

Ten groups of mice were exposed to either a single (30 Gy) or multiple (six fractions of 6 Gy) X-ray doses to the leg. Eight of these groups had the irradiated leg made hyperthermic for 45 min immediately following the X irradiation to temperatures of 37 to 43 degrees C. Eight control groups had their legs made hyperthermic with a single exposure or six exposures to heat as the only treatment. In mice exposed to radiation only, the postexposure subcutaneous temperature was 36.0 +/- 1.1 degrees C. Hyperthermia alone was not carcinogenic. At none of the hyperthermic temperatures was the incidence of tumors in the treated leg different from that induced by X rays alone. The incidence of tumors developing in anatomic sites other than the treated leg was decreased in mice where the leg was exposed to hyperthermia compared to mice where the leg was irradiated. A systemic effect of local hyperthermia is suggested to account for this observation. In mice given single X-ray doses and hyperthermia, temperatures of 37, 39, or 41 degrees C did not influence radiation damage as measured by the acute skin reactions. A hyperthermic temperature of 43 degrees C potentiated the acute radiation reaction (thermal enhancement factor 1.1). In the group subjected to hyperthermic temperatures of 37 or 39 degrees C and X rays given in six fractions, the skin reaction was no different from that of the group receiving X rays alone. Hyperthermic temperatures of 41 and 43 degrees C resulted in a thermal enhancement of 1.16 and 1.36 for the acute skin reactions. From Day 50 to Day 600 after treatment, the skin reactions showed regular fluctuations with a 150-day periodicity. Following a fractionated schedule of combined hyperthermia and X rays, late damage to the leg was less than that following X irradiation alone. Mice subjected to X rays and hyperthermic temperatures of 41 and 43 degrees C had a lower median survival time than the mice treated with hyperthermia alone. This effect was not associated with tumor incidence.     

Comparative study of the effects of hyperthermia and BCNU on BCNU-sensitive and BCNU-resistant 9L rat brain tumor cells

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU)-sensitive and BCNU-resistant 9L rat brain tumor cells were treated with BCNU at graded temperatures between 37 and 44 degrees C. The cytotoxic effects of hyperthermia alone on both cell lines were the same. Treating both cell lines with BCNU at temperatures above 37 degrees C caused a progressive increase in cell kill. All survival curves for drug-sensitive cells had shoulders followed by a region of exponential cell kill; dose enhancement ratios calculated at the 10% survival level ranged from 1.7 to 3.0. Survival curves for drug-resistant cells were exponential without a shoulder; dose enhancement ratios ranged from 3.3 to 8.4. For each cell line, a similar amount of the increased cell kill could be explained on the basis of the increases concentration of reactive species produced by hydrolysis of BCNU at elevated temperatures. The amount of cell kill that cannot be explained on this basis, however, suggests that factors other than an increase in the concentration of reactive species at higher temperatures are involved in the enhanced cell killing. Possible mechanisms include a heat-induced change in the structure of DNA chromatin and the effect of isocyanate deactivation of repair enzymes, both of which could lead to an increase in the number of crosslinks formed and therefore to an increase in cytotoxicity.     

p21+/+ (CDKN1A+/+) and p21-/- (CDKN1A-/-) human colorectal carcinoma cells display equivalent amounts of thermal radiosensitization

The mechanism of thermal radiosensitization is related to the inhibition of repair of radiation-induced DNA damage by heat. Due to the interaction of the gene p21/WAF1/CIP1 (now known as CDKN1A) with a variety of DNA repair proteins, its involvement in thermal radiosensitization was investigated. Two isogenetic human colorectal cancer cell lines with wild-type TP53 status were used. The 80S4 cell line was deficient in CDKN1A and the HCT116 cells were CDKN1A proficient. Both cell lines were significantly more sensitive to 44 degrees C than 42 degrees C heating (P < 0.01), and both cell lines expressed thermotolerance for heating times longer than about 2 h at the lower temperature. There were no significant differences in the X-radiation response of the two cell lines. Further, the two cell lines displayed similar cell survival levels after hyperthermia given before or after X radiation for both hyperthermia temperatures. Comparison of thermal enhancement ratios confirmed that there was no difference in the amount of thermal radiosensitization induced in the two cell lines. The induction and subsequent repair of DNA double-strand breaks, as measured by clamped homogeneous gel electrophoresis, was also the same in both cell lines. These findings strongly suggest that the gene CDKN1A does not play an important role in the expression of thermal radiosensitization.     

The effect of hyperthermia on the sodium-potassium pump in Chinese hamster ovary cells

The effect of hyperthermia on the Na+-K+ pump was determined by measuring influx and efflux of 86Rb+ in Chinese hamster ovary cells from 31 to 50 degrees C. The maximum initial rate of ouabain-sensitive influx increased with temperature between 31 and 45 degrees C although Km increased significantly above 37 degrees C, implying a diminished affinity of the transport protein for its substrate. The changes in the kinetics of influx at temperatures up to 45 degrees C were rapidly reversible on return to 37 degrees C. Above 45 degrees C an irreversible decrease in 86Rb+ uptake was observed. Efflux of 86Rb+ increased from 31 to 40 degrees C but above 43 degrees C showed a small but significant decrease. The study of 86Rb+ influx after varying times of exposure to elevated temperatures showed that the Na+-K+ pump remains functional in cells which are reproductively dead. We have shown that although the kinetics of K+ transport are sensitive to temperature changes in the range used in clinical hyperthermia, the inactivation of the Na+-K+ pump is not a primary event in cell killing.     

Time-temperature analyses of cell killing of synchronous G1 and S phase Chinese hamster cells in vitro

Time-temperature analyses of durations of heating required to achieve isosurvival were used to compare hyperthermic cell killing of synchronous Chinese hamster ovary (CHO) cells heated in G1 or S at temperatures of 42 to 45.5 degrees C. G1 populations were obtained by incubation of mitotic cells for 90 min at 37 degrees C. S phase populations were obtained by incubation of mitotic cells for 12 h at 37 degrees C in medium supplemented with 2 micrograms/ml aphidicolin, a reversible inhibitor of DNA alpha polymerase; S phase survival was also determined in an aphidicolin-free system by using high specific activity [3H]thymidine. In both systems, the thermosensitivity was similar and decreased as the cells progressed from early S phase, in agreement with earlier studies (R. A. Read, M. H. Fox, and J. S. Bedford. Radiat. Res. 98, 491-505 (1984]. A comparison of Arrhenius plots of the inverse of durations of heating required to achieve isosurvival for cells heated in G1 or S phase showed similar temperature dependence above 43.5 degrees C, yet the plots for heat-sensitive S phase cells were offset from those for heat-resistant G1 cells by about 1.5 degrees C, i.e., S phase cells respond to 43 degrees C with a rate similar to that observed in G1 cells heated at 44.5 degrees C. Using least-squares regression of the semilog plots, the curves were analyzed either as continually bending curves or as two straight lines with a break at 43.5 degrees C. When the data were analyzed using two straight lines, no significant differences in the slopes of the time-temperature plots of G1 or S phase cells were observed. A quantitative comparison between the two methods of data analysis demonstrated that in both phases the data were better fit with a continuously curving line, rather than two straight lines.     

Hyperthermia can differentially modulate the repair of doxorubicin-damaged DNA in normal and cancer cells

Hyperthermia can modulate the action of many anticancer drugs, and DNA repair processes are temperature-dependent, but the character of this dependence in cancer and normal cells is largely unknown. This subject seems to be worth studying, because hyperthermia can assist cancer therapy. A 1-h incubation at 37 degrees C of normal human peripheral blood lymphocytes and human myelogenous leukemia cell line K562 with 0.5 microM doxorubicin gave significant level of DNA damage as assessed by the alkaline comet assay. The cells were then incubated in doxorubicin-free repair medium at 37 degrees C or 41 degrees C. The lymphocytes incubated at 37 degrees C needed about 60 min to remove completely the damage to their DNA, whereas at 41 degrees C the time required for complete repair was shortened to 30 min. There was also a difference between the repair kinetics at 37 degrees C and 41 degrees C in cancer cells. Moreover, the kinetics were different in doxorubicin-sensitive and resistant cells. Therefore, hyperthermia may significantly affect the kinetics of DNA repair in drug-treated cells, but the magnitude of the effect may be different in normal and cancer cells. These features may be exploited in cancer chemotherapy to increase the effectiveness of the treatment and reduce unwanted effects of anticancer drugs in normal cells and fight DNA repair-based drug resistance of cancer cells.     

Sensitization to the cytotoxicity of adriamycin by verapamil and heat in multidrug-resistant Chinese hamster ovary cells.

Development of multidrug resistance to anticancer agents is a major limitation for the success of cancer chemotherapy. The chemosensitizer verapamil increases intracellular accumulation of drugs such as adriamycin in certain multidrug-resistant cell lines. When combined with verapamil, hyperthermia should be able to alter membrane permeability to adriamycin and to enhance the cytotoxicity of the drug. Verapamil increased the cytotoxicity of adriamycin in multidrug-resistant Chinese hamster ovary cells (CH(R)C5) but not in drug-sensitive cells (AuxB1). Hyperthermia (42 degrees C) alone clearly increased the cytotoxicity of adriamycin in AuxB1 cells. There was also a small increase in CH(R)C5 cells at 42 and 43 degrees C. In drug-resistant cells, the cytotoxicity of adriamycin increased considerably when verapamil was combined with heat. This effect was dependent on temperature and increased with time of incubation. At 37 degrees C, verapamil increased the uptake of adriamycin in CH(R)C5 cells, while drug efflux decreased. When verapamil was combined with hyperthermia, drug efflux decreased even further. These results led to an overall increase in intracellular accumulation of the drug. In drug-sensitive cells, hyperthermia increased both the uptake and efflux of adriamycin, but verapamil had no effect. Verapamil plus heat increased the cytotoxicity of adriamycin in drug-resistant cells, and this was accompanied by altered permeability of the membrane to the drug. Hyperthermia combined with verapamil could be beneficial by increasing the effectiveness of adriamycin in the elimination of multidrug-resistant cells in a localized target region.     

Effect of thermotolerance on thermal radiosensitization in hepatoma cells

The interaction between hyperthermia and X irradiation was determined in cultured Reuber H35 hepatoma cells with different states of thermosensitivity. Incubation at 41 degrees C followed by 4-Gy X rays resulted after 2 hr in a stabilization of cell survival for heat or plus X rays, with a maximum synergism factor of 1.6. Thermotolerance did not develop during incubation at 41.7 or 42.5 degrees C. When heat treatment of cells was followed by irradiation, the synergism factor for thermal radiosensitization increased with both the amount of thermal cell killing and the amount of X-ray cell killing; the influence of thermal exposure on the synergism factor was greater than that of the X-ray dose. Cells were made thermotolerant either by incubation at 42.5 degrees C for 30 or 60 min followed by an interval at 37 degrees C, or by continuous incubation at 41 degrees C. In both cases thermotolerance was measured by incubation at 42.5 degrees C. No difference was observed between the maximum thermotolerance achieved with both methods. When cells were irradiated in addition to the second heat treatment, thermal radiosensitization was strongly reduced concomitant with the decreased sensitivity to killing by heat.     

Effects of hyperthermia on intracellular calcium concentration and responses of cancerous mammary cells in culture.

Effects of hyperthermia on the intracellular calcium concentration (Cai) of an established mouse breast cancer cell line, MMT060562, were studied using fura-2 fluorescence microscopy and the whole-cell clamp technique. A sudden change of temperature from 37 to 45 degrees C induced a transient increase in the fluorescence ratio permeability of the cell membrane and inward current. Deletion of extracellular calcium abolished the fluorescence ratio response to the rise in temperature. Cai of some cells increased after hyperthermia treatment at 44-48 degrees C for 20 min, but the average increase of Cai was negligible. After hyperthermia treatment, spontaneous oscillation of Cai, chemical responses to ATP and bradykinin and the mechanically-induced spreading response diminished. However, the mechanically induced increase of Cai within the stimulated cell remained even after hyperthermia treatment. Suppression of the ATP-induced Cai response recovered to about half the original level within 12 h. Blockage of protein synthesis with cycloheximide (100 microM) had no effect on the recovery. The D-myo-inositol 1,4,5-triphosphate (IP3)-dependent increase of Cai remained intact even after hyperthermia treatment. It is concluded that hyperthermia treatment increases both the permeability of the cell membrane and Cai, but decreases the sensitivity of cells to ATP and bradykinin, presumably due to modification of the signal transduction mechanism.     

Improved preferential tumor hyperthermia with regional heating and systemic blood cooling: a balanced heat transfer method

Absorption of power in large body volumes can occur with some approaches used for hyperthermia treatment of cancer. A systemic heat absorption rate exceeding the heat dissipation rate can lead to systemic temperature elevation that limits the magnitude and duration of application of power and hence the degree of preferential tumor temperature rise. We describe a hyperthermia approach consisting of regional electromagnetic power absorption and extracorporeal blood cooling with regulation of both systemic heat absorption and dissipation rates ("balanced heat transfer"). A test of this approach in five dogs with nonperfused tumor models demonstrated intratumoral temperatures greater than 42 degrees C, while systemic temperature remained at 33 degrees C and visceral temperatures within the heated region equilibrated between 33 and 42 degrees C. Solutions of the bioheat transfer equation were obtained for a simplified model with a tumor perfusion rate lower than surrounding normal tissue perfusion rate. In this model, the use of arterial blood temperatures less than 37 degrees C allowed higher power densities to be used, for given normal tissue temperatures, than when arterial temperature was greater than or equal to 37 degrees C. As a result, higher intratumoral temperatures were predicted. Control of arterial blood temperature using extracorporeal cooling may thus (1) limit systemic temperature rise produced by regional heating devices and (2) offer a means of improving intratumoral temperature elevations.     

Thermotolerance and thermosensitization in CHO and R1H cells: a comparative study

In CHO and R1H cells thermotolerance was induced by a pre-incubation at 40 degrees C, by an acute heat shock at 43 degrees C followed by a time interval at 37 degrees C, and during continuous heating at 42 degrees C. Thermotolerance, which was tested at 43 degrees C, primarily causes an increase in D0 of the heat-response curve. The degree of maximum thermotolerance was found to be generally more pronounced in CHO than in R1H cells, but the time interval at 37 degrees C, as well as at 40 degrees C, to reach this maximum level was the same in both cell lines. CHO and R1H cells could be sensitized to 40 degrees C by a pre-treatment at 43 degrees C. When compared for the same survival rate after pre-treatment at 43 degrees C alone the degree of thermosensitization was about the same in both cell lines. In either cell line thermosensitization was found to be suppressed when cells were made thermotolerant by a previous incubation at 40 degrees C for 16 hours.     

Hyperthermic potentiation of chromosome aberrations by anticancer antibiotics

In view of the success of hyperthermia as a modality in cancer treatment, we have studied its effect on chromosomes in combination with anticancer antibiotics. Three classes of chemicals, one with a non-delayed type of effect (adriamycin), one with a delayed type of effect (mitomycin C), and one with a truely radio-mimetic effect (bleomycin) were selected for study on human lymphocytes and Chinese hamster K-1 cells. Propane sultone was also included because its effect on plants is suppressed by hyperthermia. The data show increased because its effect on plants is suppressed by hyperthermia. The data show increased potential of these chemicals to induce chromosome aberrations when applied at temperatures higher than 37 degrees C, irrespective of the phase of cell cycle. The potentiation may be due to true synergism (bleomycin) of facilitation of entry of larger quantities of the drug (adriamycin). No potentiating effect was observed on the induction of sister chromatid exchanges (SCEs).     

Low-temperature pausing of cultivated mammalian cells

There are currently two methods for maintaining cultured mammalian cells, continuous passage at 37 degrees C and freezing in small batches. We investigated a third approach, the "pausing" of cells for days or weeks at temperatures below 37 degrees C in a variety of cultivation vessels. High cell viability and exponential growth were observed after pausing a recombinant Chinese hamster ovary cell line (CHO-Clone 161) in a temperature range of 6-24 degrees C in microcentrifuge tubes for up to 3 weeks. After pausing in T-flasks at 4 degrees C for 9 days, adherent cultures of CHO-DG44 and human embryonic kidney (HEK293 EBNA) cells resumed exponential growth when incubated at 37 degrees C. Adherent cultures of CHO-DG44 cells paused for 2 days at 4 degrees C in T-flasks and suspension cultures of HEK293 EBNA cells paused for 3 days at either 4 degrees C or 24 degrees C in spinner flasks were efficiently transfected by the calcium phosphate-DNA coprecipitation method, yielding reporter protein levels comparable to those from nonpaused cultures. Finally, cultures of a recombinant CHO cell line (CHO-YIgG3) paused for 3 days at 4 degrees C, 12 degrees C, or 24 degrees C in bioreactors achieved the same cell mass and recombinant protein productivity levels as nonpaused cultures. The success of this approach to cell storage with rodent and human cell lines points to a general biological phenomenon which may have a wide range of applications for cultivated mammalian cells.     

Thermal analysis of CHL V79 cells using differential scanning calorimetry: implications for hyperthermic cell killing and the heat shock response

Differential scanning calorimetry (DSC) was used to assay thermal transitions that might be responsible for cell death and other responses to hyperthermia or heat shock, such as induction of heat shock proteins (HSP), in whole Chinese hamster lung V79 cells. Seven distinct peaks, six of which are irreversible, with transition temperatures from 49.5 degrees C to 98.9 degrees C are detectable. These primarily represent protein denaturation with minor contributions from DNA and RNA melting. The onset temperature of denaturation, 38.7 degrees C, is shifted to higher temperatures by prior heat shock at 43 degrees and 45 degrees C, indicative of irreversible denaturation occurring at these temperatures. Thus, using DSC it is possible to demonstrate significant denaturation in a mammalian cell line at temperatures and times of exposure sufficient to induce hyperthermic damage and HSP synthesis. A model was developed based on the assumption that the rate limiting step of hyperthermic cell killing is the denaturation of a critical target. A transition temperature of 46.3 degrees C is predicted for the critical target in V79 cells. No distinct transition is detectable by DSC at this temperature, implying that the critical target comprises a small fraction of total denaturable material. The short chain alcohols methanol, ethanol, isopropanol, and t-butanol are known hyperthermic sensitizers and ethanol is an inducer of HSP synthesis. These compounds non-specifically lower the denaturation temperature of cellular protein. Glycerol, a hyperthermic protector, non-specifically raises the denaturation temperature for proteins denaturing below 60 degrees C. Thus, there is a correlation between the effect of these compounds on protein denaturation in vivo and their effect on cellular sensitivity to hyperthermia.     

The effect of 45 degrees C hyperthermia on the membrane fluidity of cells of several lines.

The membrane fluidity of cells of human (AG1522 human foreskin fibroblasts), rodent [Chinese hamster ovary (CHO) and radiation-induced mouse fibrosarcoma], and feline (Crandall feline kidney) cell lines after heating at 45 degrees C was measured by flow cytometry. In addition, a heat-resistant variant of radiation-induced mouse fibrosarcoma cells and two heat-sensitive CHO strains were studied. Fluorescence polarization of the plasma membrane probe trimethylammonium-diphenylhexatriene was used as a measure of membrane fluidity. The sensitivity of all cell lines to 45 degrees C hyperthermia was compared. The baseline membrane fluidity varied among the cell lines, but did not correlate with sensitivity to hyperthermia. However, CHO cells, especially the heat-sensitive mutants, had the largest increase in membrane fluidity after heating at 45 degrees C, while the heat-resistant mouse fibrosarcoma variants and Crandall feline kidney cells resisted changes in fluidity. In general, the more resistant the cell line was to killing by heat, the more resistant it was to changes in membrane fluidity.     

Sensitization to the cytotoxicity of melphalan by ethacrynic acid and hyperthermia in drug-sensitive and multidrug-resistant Chinese hamster ovary cells

The ability of physical and pharmacological modulators to increase the cytotoxicity of melphalan was investigated in Chinese hamster ovary cells using a clonogenic cell survival assay. Hyperthermia has potential for use in cancer treatment, particularly as an adjuvant to chemotherapy or radiotherapy. Ethacrynic acid is a glutathione S-transferase inhibitor and also undergoes conjugation with glutathione. Interactions between hyperthermia (41-43 degrees C), ethacrynic acid and melphalan were evaluated in multidrug-resistant (CH(R)C5) cells with overexpression of P-glycoprotein (33.69-fold), and in drug-sensitive (AuxB1) cells. GST alpha was expressed at a higher level (3.65-fold) in CH(R)C5 cells than in sensitive cells, whereas levels of isoforms pi and mu were the same. GST pi was the most highly expressed isoform in the two cell populations. Ethacrynic acid was cytotoxic at elevated temperatures, while it caused little or no cytotoxicity at 37 degrees C. This effect occurred in drug-resistant and drug-sensitive cells, and attributes thermosensitizing properties to ethacrynic acid. Ethacrynic acid (20 microM) alone did not alter the cytotoxicity of melphalan at 37 degrees C. Hyperthermia potentiated drug cytotoxicity in cells, both with and without ethacrynic acid treatment. Ethacrynic acid could be useful in cancer treatment by acting as a thermosensitizer when combined with heat and by enhancing the cytotoxicity of melphalan at elevated temperatures. A major advantage arising from the use of regional hyperthermia is the ability to target drug cytotoxicity to the tumor volume. A useful finding is that ethacrynic acid, heat and/or melphalan are also effective against multidrug-resistant cells with overexpression of P-glycoprotein.     

Changes in bleb formation following hyperthermia treatment of Chinese hamster ovary cells

Chinese hamster ovary cells in suspension cultures were heated for various times at 41.5, 43.5, and 45.5 degrees C, and quantitative determinations of microblebbing and macroblebbing of the cell membrane were performed for cells maintained at 4, 25, and 37 degrees C after hyperthermia. The percentage of cells with blebs following heating at 45.5 degrees C was dependent upon the duration of heating with increases from 40% for 5 min to 90% for 30 min. Cells exposed to lower temperatures exhibited less blebbing which was not quantifiable. The changes in bleb formation following 45.5 degrees C were dependent upon the posthyperthermia temperature: a slight decrease of macroblebbing at 25 degrees C, a decrease to 50% by 2 h at 37 degrees C, and a sharp decrease of macroblebbing to less than 10% by 1 h at 4 degrees C. Microblebbing increased slightly at 37 degrees C. When cells were transferred rapidly from the 4 degrees C posthyperthermia incubation to 37 degrees C, the bleb formation percentages returned rapidly to the higher levels which existed before posthyperthermia incubation at the lower temperatures. Gamma irradiation of 20 and 50 Gy produced only a small increase in microblebbing at longer periods (5 to 6 h) but no increase in macroblebbing. The survival of cells heated for 20 min at 45.5 degrees C was decreased 40% for suspension cells maintained at 4 degrees C for 2 to 3 h before incubation at 37 degrees C for colony formation compared to cells immediately incubated at 37 degrees C after heating. The survival of cells maintained at 25 degrees C after heating was not altered in comparison.     

Effect of hyperthermia on the frequency of sister-chromatid exchanges in patients with cancer of cervix uteri

The frequencies of sister-chromatid exchanges (SCE) were studied in patients with cancer of the cervix uteri and normal controls at 37 degrees C and 40 degrees C. At 37 degrees C the mean frequency of SCE was found to be 8.26 +/- 1.91 in untreated patients with cervical cancer and 7.91 +/- 1.68 in cancer patients treated with radiotherapy; these values were significantly higher than the control value of 5.34 +/- 1.28 exchanges. Increase of the growth temperature to 40 degrees C elevated the SCE frequency to 11.95 +/- 2.12 in patients without radiotherapy treatment, 13.37 +/- 2.17 in patients with radiotherapy treatment and 7.82 +/- 1.84 in normal controls. These data indicate that there is a differential induction of SCEs by hyperthermia in the lymphocytes of control women and patients with cancer of the cervix uteri.