Electron Affinic Sensitization: V. Radiosensitization of Hypoxic Bacteria and Mammalian Cells in Vitro by Some Nitroimidazoles and Nitropyrazoles

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.

mentioning

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

“…SINCE THE FIRST DEMONSTRATION that nitroimidazoles can be effective radiosensitizers of hypoxic cells in vitro and in vivo (Foster & Willson, 1973;Begg et al, 1974;Asquith et al, 1974;Denekamp et al, 1974) 3 drugs have undergone a battery of investigations and are now being tested clinically. Misonidazole (MISO), a 2-nitroimidazole, and Ro 05-9963, the desmethyl metabolite, are more effective sensitizers than the 5-nitroimidazole, metronidazole, but their clinical use is limited by neurotoxicity.…”

mentioning

confidence: 99%

Comparative studies of hypoxic-cell radiosensitization using artificially hypoxic skin in vivo

Denekamp¹,

Michael²,

Minchinton³

et al. 1982

Summary.-The survival of epidermal cells in vivo has been used to assess potential radiosensitizers. Mouse skin was made acutely hypoxic for the irradiations, to give radioprotection by a factor of 2-7-3-0. Several concentrations of each drug were used to determine whether any of them were more effective sensitizers than misonidazole. The SER at each concentration was determined from radlobiological dose-response curves. The blood concentration and toxicity of the compounds were also determined. The sensitizing efficiency, assessed in several ways, indicated that only Ro 03-8799 gave significantly greater sensitization than misonidazole, and then only when assessed by comparing the compounds on the basis of equimolar blood concentrations. If the comparison of efficiency was made in terms of LDso the ranking order changed.

“…Increased cell killing is also obtained if cells are given high concentrations of MISO (50 mM) in air during exposure to melphalan. 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

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.