![]() The addition of both hyperthermia and misonidazole to radiation more than overcame the relative resistance of the dim subpopulation to 10 Gy. Analysis of the cytotoxicity achieved by these treatments in Hoechst 33342 dye-selected tumor subpopulations demonstrated that, whereas radiation was more toxic toward bright (presumably euoxic) cells, misonidazole, hyperthermia, and the combination were significantly more toxic toward dim (presumably hypoxic) cells. In vivo, treatment of the FSaIIC tumor with misonidazole (1 g/kg) and/or local hyperthermia (43 degrees C for 30 min to the tumor-bearing limb) in conjunction with radiation (10, 20, or 30 Gy) yielded a radiation dose modifying factor for misonidazole of 1.32, for hyperthermia of 1.38, and for the combination of 2.06 (probably additive). Similarly, the dose modifying effect of misonidazole on single radiation fractions in vitro was also reduced at pH 6.45 versus pH 7.40 (2.60 versus 2.40, p less than 0.01). ![]() Unexpectedly, exposure to misonidazole at 42 degrees C or 43 degrees C and pH 6.45 caused no significant increase in cytotoxicity over that attributable to hyperthermia alone. At pH 6.45 and 37 degrees C, misonidazole was less cytotoxic toward both euoxic and hypoxic cells than at pH 7.40. At 42 degrees C and 43 degrees C at pH 7.40, a less than 2-fold increase in cytotoxicity was observed in both normally oxic and hypoxic cells as compared with 37 degrees C. At doses of 5-500 microM for 1 hr, misonidazole was 1.5- to 2-fold more toxic toward hypoxic versus euoxic cells at 37 degrees C and pH 7.40. The effect of pH on misonidazole-induced cell killing at normal and elevated temperatures and on radiosensitization by misonidazole at 37 degrees C was assessed in FSaIIC fibrosarcoma cells in vitro. In the same way, the frequency and the amplitude of spontaneous field discharges in low-calcium solution decreased from pH 7.40 to 7.15 and increased from pH 7.40 to 7.80.(ABSTRACT TRUNCATED AT 250 WORDS) The frequency of spontaneous field discharges in the presence of bicuculline significantly decreased by reducing pH from 7.40 to 7.30 and continuously increased from pH 7.40 to 7.80. Electrically evoked field potentials were markedly depressed from pH 7.15 to 7.00 and enhanced from pH 7.60 to 7.80. The effects of changing o on electrically evoked field potentials and spontaneous field discharges were studied in the range from pH 7.00 to 7.80. An alkaline transient was superimposed on the acid transient only when increases of o exceeded 1.5 mM. However, spontaneous field discharges in low-calcium solution in which synaptic transmission is reduced were associated with acid transients of up to 0.02 pH units lasting 2-20 s. The time to the maximal amplitude of the alkaline transients and the time to maximal increases of o were in the same range, concurring with the assumption that alkaline transients are due to a proton influx through cationic channels. About 10-fold smaller alkaline transients were induced by spontaneous field discharges in the presence of bicuculline. Repetitive electrical stimulation and application of glutamate or GABA were associated with prominent alkaline transients of up to 0.2 pH units lasting 2-10 s followed by smaller acid transients lasting up to 4 min. Changes of extracellular proton concentration (o) and K+ activity (o) were simultaneously measured by ion-sensitive microelectrodes in the CA3 region of guinea pig hippocampal slices.
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