Enhancement of the cytotoxicity of radiosensitizers by modest hyperthermia: the electron-affinity relationship

Abstract

Summary.-The cytotoxicity of 3 electron-affinic radiosensitizers has been studied in Chinese hamster V-79 cells as a function of pH and modest hyperthermia. When equitoxic concentrations were used and temperature was increased from 34 to 41°C metronidazole, the compound with the lowest electron affinity showed the greatest enhancement of hypoxic-cell toxicity, and nitrofurantoin, the compound with the highest electron affinity, the least. The results can be explained if the mechanisms of toxicity involves a redox reaction, since it would be expected that the least toxic compound (lowest electron affinity) would have the largest activation energy and hence the greatest temperature effect. This appears to hold for these 3 compounds.Experiments also showed that nitrofurantoin which exhibits no increase in toxicity when the temperature was increased from 37 to 41°C at pH 7*4, showed an increase in toxicity for the same temperature change at the pH of 7-0 and 6-6.Under aerobic conditions only metronidazole showed significant toxicity at 41°C, where the differential between aerobic and hypoxic cell toxicity was minimal, both at pH 7*4, and at the low pH values of 7-0 and 6-6.In the clinical setting there is evidence that tumour cells are at a lower pH than their surrounding normal tissues. Hypoxic-cell cytotoxicity is enhanced at low pH, and even further enhanced at low pH in combination with a temperature of 41°C. However, this finding correlates conversely with electron affinity. Thus, the radiosensitizer (and trichomonicide) metronidazole is most influenced by low pH and high temperature with the nitroimidazole, misonidazole, demonstrating a smaller enhancement due to higher temperatures.

Enhancement of hyperthermochemotherapy for human gastric cancer in nude mice by thermosensitization with nitroimidazoles

“…Siemann (1982) reported that the combination of CCNU and MISO exerted an antitumour effect on murine tumours, but this was not the case with CCNU and MTR. In contrast, Rajaratnam et al (1982) reported that in a hyperthermic treatment at 41°C, MISO exhibited a smaller degree of cytotoxicity than MTR, when both these drugs were given in equitoxic concentrations. As shown in Table I, MTR is clearly less effective than MISO in combination with MCC.…”

“…Stone (1978) and Honess et al (1978) reported that in in vivo experiments with murine tumours, local hyperthermia combined with MISO resulted in a delay in tumour growth. Hall et al (1977) and Rajaratnam et al (1982) reported that malignant cells cultured at high temperature showed a marked decrease in growth rate in the presence of MISO or MTR. In the present study, the combination of hyperthermia and MTR did not enhance the antitumour activity, while hyperthermia combined with MISO and MMC resulted in a significant delay in tumour growth.…”

Hyperthermia Enhances the Cytotoxicity against Hypoxic Cells of RP-170, a New 2-Nitroimidazole Nucleoside Hypoxic Cell Sensitizer

“…Hyper thermia may increase cell target producing intermediates that contribute to the cytotoxcity of RP-170. Further more, it is conceivable that chemical activation ofRP-170 is increased by the addition of thermal energy and that cellular repair systems are inhibited [4,5].…”

“…The use of radiation sensitizing agents, including mi sonidazole (MISO) [1], and chemotherapeutic agents [2] in conjunction with hyperthermia [3][4][5] has shown prom ise both experimentally and clinically. Such a combined modality is more effective for disseminated malignant disease such as leukemia than for solid tumors [6].…”