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Effects of Hyperthermia on Survival and Progression of Chinese Hamster Ovary Cells¹

Department of Radiology and Radiation Biology, Colorado State University, Fort Collins, Colorado 80523 [S. A. S., L. E. H., W. C. D.]; Biophysical and Instrumentation Group, Los Alamos Scientific Laboratory, Los Alamos, New Mexico 87544 [M. R. R.]; and Biomedical Division, Lawrence Livermore Laboratory, Livermore, California 94550 [J. W. G.]

In general, the survival of Chinese hamster ovary cells exposed to hyperthermic temperatures of 42.5–46.0° decreases exponentially as a function of duration of heat exposure in a manner quite similar to survival as a function of radiation dose. The data indicate that above 43° a 1° change in temperature requires a 2-fold change in time to achieve the same degree of killing, whereas below 43° the same 2-fold change in time requires only a 0.5° change in temperature for the same effect. An Arrhenius-type plot of the logarithm of the rate of killing as a function of reciprocal temperature exhibits linearity with a change in slope at 43°. This change in slope suggests either a change in the mechanism of cell killing below this temperature or a manifestation of thermal tolerance that is readily observed when the duration of heating exceeds 4 to 5 hr.

Thermotolerance to 45.5°, as evidenced by a 3- to 4-fold increase in ₀, is observed in synchronous G₁ cells exposed to heat 20 hr after an initial heat dose. This thermotolerance develops, although no progression of cells into S phase occurs during this period. In addition, thermotolerance develops in both asynchronous and synchronous G₁ cells exposed to single heat doses between 41.5 and 42.5° for periods exceeding 4 to 5 hr, i.e., survival decreases exponentially as a function of duration of heating up to 4 to 5 hr, after which survival decreases very little. At 42.0–42.5°, survival is extremely sensitive to changes in temperature, with as much as a 10-fold difference in survival for a 0.1° difference in temperature with heat exposures greater than 4 hr. The above data indicate the importance of careful treatment design and precise temperature control if hyperthermia is to be used for cancer therapy.

No progression of synchronous G₁ cells into S phase is observed for cells continuously exposed to temperatures of 42.0° and above. However, computer simulation of sequential DNA histograms from flow cytometry of synchronous cells continuously exposed to 41.5° indicates that cell cycle delays of 5.4 and 2.4 hr for G₁ and S, respectively, occurred for cells for which exposure began in G₁, and delays of 0.5 and 5.4 hr for S and G₂ plus mitosis, respectively, occurred for cells for which exposure began in late S. Normal cell cycle phase transit times for G₁, S, and G₂ plus mitosis are 4.3, 7.1, and 2.4 hr, respectively.

In addition, mitotic indices and increases in cell number of asynchronous populations of cells continuously exposed to 41.5° indicate that entry into mitosis is delayed for approximately 2 hr. Following this delay, cells begin to enter mitosis and accumulate from 2 to 6 hr in metaphase; after about 6 hr, they begin to progress into G₁. However, comparison of flow cytometry data and mitotic index data suggests that during the initial 6 hr of heating, the majority of cells accumulating in G₂ plus mitosis are actually delayed in G₂.

¹ Supported in part by Grants CA08618 and CA14533 from the National Cancer Institute, Department of Health, Education and Welfare, and was performed under the auspices of Contract W-7405-ENG-48 from the Energy and Research Development Administration.

Received 7/14/77. Accepted 11/ 8/77.

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