Relationship between Hyperthermic Cell Killing and Protein Denaturation by Alcohols

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Abstract
The monohydric alcohols methanol, ethanol, 2-propanol and tert-butanol dramatically sensitive V79 Chinese hamster lung cells to hyperthermia. For concentrations < 3% alcohol by weight, the rate of cell inactivation (k) appears to vary exponentially as a function of alcohol concentration. The degree of sensitization increases with increasing chain length, and for a constant concentration the ratio of the k values is 1:1.3:1.8:3.1 for methanol, ethanol, 2-propanol and t-butanol, respectively. The dihydric alcohol ethylene glycol (at < 4% by weight) has no effect on cell survival. The trihydric alcohol glycerol protects cells from hyperthermia and 10% glycerol decreases k from the control value of 7.87 .times. 10-4/s at 43.0.degree. C to 1.97 .times. 10-4/s. Mono-, di- and trihydric alcohols have similar effects on the rate of protein denaturation. Membrane lipid fluidity of V79 cells was determined from 23-63.degree. C by measuring the rotational correlation time of the spin label 2,2-dimethyl-5-dodecyl-5-methyloxazolidine-N-oxide (2N14). A straight line was found for the Arrhenius plot of .tau.c with an activation energy of 4.82 .+-. 0.07 kcal/mol. No break or bend is present that could signify a membrane-phase transition near the onset of hyperthermic killing. The membrane fluidizing ability of the monohydric alcohols was measured and found not to correlate well with the degree of heat sensitization by the same alcohols. From the Arrhenius plot of the rate of cell killing from 42.0-46.8.degree. C, the enthalpy (.DELTA.H.noteq.) and entropy (.DELTA.S.noteq.) of activation were found to be 146 .+-. 9 kcal/mol and 388 cal/mol .degree.K, respectively. These values are consistent with protein denaturation (or possibly the denaturation of some other macromolecule) being the rate-limiting step in hyperthermic cell killing. [Hyperthermia alone or in combination with radiation or chemotherapy appears to be of considerable use in cancer therapy.].

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