Hypoxic radiation sensitivity

Cisplatin was first characterized as a radiation sensitizer using hypoxic Bacillus megaterium spores (53). Radiation sensitization by cisplatin was confirmed in vegetative Escherichia coli with a maximum sensitizer enhancement ratio of 1.77 in anoxic bacteria at a cisplatin concentration of 50 uM (54). Zimbrick et al. (55) extended these studies to other platinum complexes. The earliest studies in mammalian cells used hypoxic V-79 Chinese hamster cells and showed a small radiation sensitization with 8 iM of cisplatin (56). Nias and Szumiel (57) first reported that pretreatment of Chinese hamster ovary (CHO) cells with a platinum complex could sensitize well-oxygenated cells to radiation. Wodinsky etal. (58) showed that cisplatin potentiated the effect of whole-body radiation therapy in mice inoculated intraperitoneally with P388 leukemia compared with either modality alone. Therapeutic potentiation was found in MTG-B subcutaneous tumors and intracerebral RBT when the animals were treated with cisplatin and radiation (59). 

Preclinical models have established various methods to increase the cytotoxic activity of radiation therapy. This methodology includes promoting activity against cells in the most radiation-sensitive phase of the cell cycle, the G2/M phase, and eradicating hypoxic tumor cells to decrease radioresistance. The method of radiation therapy (con-... 

Metronidazole (135) is a y-radiation sensitizer of hypoxic cells in cancer radiotherapy. Irradiation with UV light in oxygen-free neutral aqueous solution results in quantitative rearrangement to the oxadiazole (136) (Scheme 60) <87HCA171,87JCS(P1)1817>. 

Porschen W, Bosiljanoff P, Gewehr K, Muhlensiepen H, Weber HJ, Dietzel F, Feinendegen LE (1977) In vivo assay of the radiation sensitivity of hypoxic tumour cells. Influence of radiation quality and hypoxic sensitization. In Radiobiological research and radiotherapy, Vol. 1. International Atomic Agency, Vienna, pp 181-194... 

Radiation sensitizers are pharmacologic agents that increase the lethal effects of radiation when administered in concert with it. An ideal radiation sensitizer should augment the cytotoxicity of radiation applied to malignant loci but not engender enhanced killing of normal cells, operate via a mechanism that is active towards oxic and hypoxic cell regions, and have a low inherent in vivo toxicity. 

As detailed in the context of the hypoxic sensitizer discussion above, the idea that an easy-to-reduce species could function as a radiation sensitizer is not new [113-117]. Indeed, there is considerable precedent for it both in the radiation sensitization literature per se [113-115,118,125-129,132-135,138,139,142] and in classic mechanistic explanations of radiation-induced cytotoxicity [143-145]. However, as has also been made clear in the context of this earlier discourse, this idea has yet to translate into an FDA-approved XRT sensitizing product. However, as noted above, PCI-0120 (3) possesses special features that led to the consideration that it... 

Drugs to enhance radiation sensitivity are of clinical value only if there is selectivity towards the tumour compared to normal tissues unavoidably included in the radiation field in radiotherapy. The drugs discussed briefly below -hypoxic cell radiosensitizers - present such selectivity mainly because oxygen is such an efficient radio sensitizer that in well-oxygenated tissues its effect is virtually at a maximum, and added oxygen-mimetic drugs have very little additional effect. 

A high radiotherapeutic effect cannot be achieved on cells in the S-phase, which is considered to be the least radiation-sensitive phase in the cell replication cycle, or on hypoxic cells, seriously affecting the tumor s response to radiotherapy. Encouragingly, all these radioresistant cells are very sensitive to the lethal effects of hyperthermia. 

Similarly, reaction of 2-nitroimidazole with l,2-epoxy-3-methoxypropane in the presence of potassium carbonate gives misonidazole (27).This agent also has the interesting and potentially useful additional property of sensitizing hypoxic tumor cells to ionizing radiation. 

In an excellent review of the literature on the interaction between radiation and the taxanes, especially looking at the effects of paclitaxel, Milas et al.(38) outline how they came to realize that reoxygenation played such a substantial role in the potentiation of tumor radioresponse. It has been well established for years that tumors contain areas of hypoxic cells that are normally 2.5 to 3 times less sensitive to radiation than normal cells (37). Both radiation and chemotherapies can cause reoxygenation through their preferential killing of those oxygenated cells that are located close to blood vessels. Milas et al. summarized observations that showed ... 

Adams GE, Flockhart IR, Smithen CE, Stratford IJ, Wardman P, Watts ME (1976a) Electron-affinic sensitization. VII. A correlation between structures, one-electron reduction potentials, and efficiencies of nitroimidazoles as hypoxic cell radiosensitizers. Radiat Res 67 9-20... 

Adams GE, Clarke ED, Flockhart IR, Jacobs RS, Sehmi DS, Stratford IJ, Wardman P, Watts ME, Parrick J, Wallace RG, Smithen CE (1979) Structure-activity relationships in the development of hypoxic cell radiosensitizers. I. Sensitization efficiency. Int J Radiat Biol 35 133-150... 

On going from a radical to RA and RDA the HFS constant of nitro group nitrogen atom grows [849, 852, 860], In connection with this the characteristics of ESR spectra of 2,4(5)-dinitro- and l-(2-hydroxyethyl)-2,4(5)-dinitroimidazoles (used as radiosensitizers selectively sensitizing hypoxic mammalian cells to the lethal effect of ionizing radiation) cause surprise [862] (Scheme 3.22). 

The second class of materials that has been the subject of clinical study in the context of XRT sensitization is the so-called hypoxic sensitizers. These agents are electron-affinic compounds that exacerbate damage induced by ionizing radiation... 

Ascorbate Potentiated Cytotoxicity of Nitroaromatic Compounds. Extensive research aimed at finding chemicals or chemical systems that will sensitize hypoxic cells, which are ordinarily very resistant to radiation or chemicals, is being conducted in the field of radiobiology. Of particular interest are the investigations (58-6J) of the catalytic effect of certain carcinogens upon the oxidation of ascorbate. 4-Nitroquinoline N-oxide (4-NQO), which is one of many compounds (52,62,63) that mediate the ascorbate-oxygen reaction, is used as an example. 

Radiosensitizing Agents - Agents which sensitize tumor cells to the lethal effects of ionizing radiation are being actively pursued. Two known radiosensitizers, metronidazole and nitrofurazone, were shown to be cytotoxic to Chinese hamster cells in the absence of radiation, but only under hypoxic conditions.82 The x-ray requirement for antitumor activity in a murine anaplastic carcinoma was reduced when metronidazole was administered orally before irradiation.83 RO-07-0582 (13), a compound... 

Another use of hyperbaric oxygenation, which has met with a certain amount of success, is in conjunction with radiotherapy for the treatment of neoplasias. This technique is based on the well-documented observation that normal and malignant tissues are less susceptible to the deleterious effects of X-irradiation when they are relatively hypoxic (G28, G29). This is true not only for mammalian cells, but for lower forms of life as well. The increased sensitivity of cells to X-irradiation in the presence of an increased oxygen tension approaches a factor of 3. This means that a smaller dose of radiation is required in the presence of oxygen to produce an effect equal to that obtained during anoxia. 

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