Effect of hyperthermia on differential cytotoxicity of a hypoxic cell radiosensitizer, Ro-07-0582, on mammalian cells in vitro

Summary.-The tumour used, designated MT1, is a more radiosensitive form of the anaplastic MT tumour previously described. No explanation for the increased radiosensitivity was found, but it was shown not to be due to infection or to a change in immunological status, growth rate or histology. The sensitivity has remained constant throughout the present work.No cytotoxicity in the tumour was observed when 1 mg/g body weight of Ro-07-0582 was injected immediately after a single dose of X-rays; indeed a small protective effect was seen.A radiosensitization enhancement of 1P5 was achieved with a relatively low drug dose of Ro-07-0582 in a 5F/4d fractionated regime.The interval between the injection of a low dose of Ro-07-0582 and the start of irradiation was found to be critical, the optimum interval being 45-60 min.The subsequent incidence of distant metastases was not increased by the use of Ro-07-0582 at the time of "primary" tumour irradiation.

Section: Tumour Changementioning

confidence: 99%

Further investigations of the effects of the hypoxic-cell radiosensitizer, Ro-07-0582, on local control of a mouse tumour

Sheldon¹,

Hill²

1977

“…The culture of V79-379A cells and the procedures for carrying out hypoxic-cell toxicity experiments have been described elsewhere (Stratford & Adams, 1977 Control cells showed a decrease in growth rate, but no loss in cell survival when the pH of the extracellular medium was decreased from 7-4 to 6 4 for a period of 60 h at 37°C. The presence of each of the drugs at the concentration chosen caused no additional effects.…”

Section: Methodsmentioning

confidence: 99%

“…The toxicity of one such drug, misonidazole (MISO), is a function of drug concentration and contact time (Hall & Roizin-Towle, 1975;Moore et al, 1976; Stratford & Adams, 1977), pH (Stratford, 1979), serum concentration and serum source (Stratford & Gray, 1978;Hall et al, 1977;Whitmore et al, unpublished data) and temperature (Stratford & Adams, 1977;Hall et al, 1977).…”

mentioning

confidence: 99%

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

Rajaratnam¹,

Adams²,

Stratford³

et al. 1982

Self Cite

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.

“…MISONIDAZOLE (MISO) is an effective radiosensitizer of hypoxic cells in vitro and in vivo (Asquith et al, 1974;Fowler & Denekamp, 1979) and is currently undergoing randomized, prospective clinical trials. It is also preferentially cytotoxic to hypoxic cells (Hall & Roizin-Towle, 1975;Moore et al, 1976;Stratford & Adams, 1977).…”

mentioning

confidence: 99%

Enhancing effect of pre-treatment of cells with misonidazole in hypoxia on their response to melphalan in air

Smith¹,

Stratford²,

Adams³

1982

Self Cite

Summary.-Pre-treatment of hypoxic cells with misonidazole (MISO) can render these cells more sensitive to a subsequent treatment with melphalan. Results in this paper show that this enhancement (or chemopotentiation) depends on the contact time and concentration of MISO, on the melphalan concentration and also on the cultural history of the cells. Damage due to hypoxic pre-incubation in MISO can be repaired if cells are subsequently aerated at 37°C. In contrast, for cells washed free of MISO and then held under N2 at 37°C, repair is much slower. No repair occurs when cells are held in air at 0°C. The kinetics and extent of repair were dependent on the cells prior culture. Thus for exponential cells repair was complete after %4 h, whereas for plateau -phase cells and cells with prior chronic hypoxia, repair was only partially complete after this time. Dithiothreitol was shown to protect partially against the enhancement of melphalan toxicity. Increased cell killing is also obtained if cells are given high concentrations of MISO (50 mM) in air during exposure to melphalan.