The interpretation of “split-dose” experiments in mammalian cells after treatment with alkylating agents

Fox, Margaret; Gilbert, C. W.; Lajtha, L. G.; Nias, A. H. W.

doi:10.1016/0009-2797(70)90011-6

Cited by 15 publications

(1 citation statement)

References 12 publications

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“…The present data would suggest that misonidazole-induced damage is not related to radiation-induced sublethal damage and that drug/radiation interaction must occur via other processes. There is conflicting evidence as to the ability of cells to repair damage caused by radiomimetic alkylating agents (Fox et al, 1970;Cleaver, 1971;Ben-Hur and Elkind, 1974b). In an instance where repair between fractionated doses has been demonstrated, it was found that this repair was considerably inhibited by treatment at 41TC (Ben-Hur and Elkind, 1974b) indicating that damage caused by radiomimetic alkylating agents also differs from that seen in cells after treatment with misonidazole.…”

Section: Discussionmentioning

confidence: 99%

Split dose cytotoxic experiments with misonidazole

Stratford¹

1978

Br J Cancer

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Summary.-The toxicity of misonidazole (1-(2-nitroimidazol-1-yl)-3-methoxy-2-propanol) towards mammalian cells in vitro has been determined as a function of 02 tension. Misonidazole under hypoxic conditions (< 10 Parts/106 02) shows the greatest toxicity. Split-dose experiments indicate that lethal damage can be "repaired" by 02, the magnitude of this repair being time dependent and a function of 02 concentration, with maximum repair in air seen after 2 h at 37°C. Unlike radiation damage this repair is not inhibited by modest hyperthermia (41°C) during the splitdose interval. The implication of these results as regards the mechanism of misonidazole toxicity under anaerobic conditions is discussed. THE use of cytotoxic agents which are specifically toxic towards hypoxic cells has likely application in combination chemotherapy and/orradiotherapy. Sutherland (1974) identified the hypoxic cell radiosensitizer, metronidazole, as being selectively toxic to the non-cycling cells in his spheroid in vitro tumour model. Subsequently, other potentially useful radiosensitizers, misonidazole, nitrofurazone, nifurpipone and nimorazole were also found to be specifically toxic to hypoxic cells (Hall and Roizin-Towle, 1975;Foster et al., 1976;Mohindra and Rauth 1976;Moore et al., 1976;Sridhar et al., 1976;Watts, 1977;Stratford and Adams, 1977;. In addition, this selective toxicity has now been associated with a wide variety of nitroaromatic compounds of high electron affinity (Adams et al., 1978).In the course of investigating the cytotoxicity of the drugs metronidazole and nitrofurazone, it was found that the toxic effect was dependent upon the 02 tension, with toxicity increasing as the 02 concentration decreased (Mohindra and Rauth, 1976). The present paper examines, in detail, the effects of 02 concentration on the toxicity of misonidazole, a drug which is presently undergoing clinical trials as a radiosensitizer (Dische et al., 1977). The influence of 02 on the repair capacity of mammalian cells treated with drug under hypoxic conditions is also studied, with a view to characterizing the mechanism of misonidazole cytotoxicity. MATERIALS AND METHODSChiniese hamster V79-379A cells were used throughout these investigatioils. Cells were maintained in spinner culture using Eagle's Minimal Essential Medium (MEM) MISONIDAZOLE TOXICITY flowed over the surface of the stirred suspension. 02 concentrations in the effluent gas were determined using a Thermox meter 02 analyser (Thermo-Lab. Instruments Inc.) and these concentrations were generally constant after 1 h. The gas flow was continued throughout the experiment. Aliquots were removed from the test cell suspensions when required and the cells assayed for colonyforming ability.For split-dose experiments, cells in contact mith misonidazole were rendered hypoxic by flowxNing 95% N2/5% C02 (< 10 parts/106 02) over stirred suspensions. When the surviving fraction was about 10-2, the flow of N2 was stopped and air/ 50// CO2 passed over the suspension. After the desired interval the gas...

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