Hypoxia in Solid Tumours and Normal Tissues: Clinical Implications

Abstract

1. Two types of hypoxia may exist in a solid tumour: (a) diffusion-limited or chronic hypoxia with the hypoxic cells mostly bordering necrosis, and (b) ischaemic or acute hypoxia due to intermittent closure of blood vessels with the distribution of hypoxic cells unrelated to necrosis. Chronically hypoxic cells are more radiosensitive than the acutely hypoxic ones. 2. Evidence of hypoxia in human solid tumours is mainly based on studies of tumour vasculature, the results of the hyperbaric oxygen clinical trials, the demonstration of the unfavourable influence of anaemia and a low arterial oxygen content on the outcome of radiotherapy. A study of the binding of the bioreductive products of 3H-misonidazole in human tumours suggests that hypoxia is not a universal finding and is likely to exist only in a proportion of tumours. 3. Some normal tissues may have radiobiological hypoxia particularly, the gut, testes, laryngeal cartilage and to a lesser extent the skin. 4. Correction of anaemia prior to radiotherapy and daily fractionation are the most practical means of controlling hypoxia. Residual clinically relevant hypoxia may, however, persist after conventional fractionation. 5. The use of carbogen (a mixture of 95% oxygen and 5% carbon dioxide) was shown to enhance the response of animal tumours to multifraction irradiation involving relatively small fractions. This enhancement could be further increased when carbogen was combined with perfluorochemicals (oxygen-carrying agents). The clinical safety of the perfluorochemicals has to be established first before they are used in repeated doses in cancer therapy. 6. Misonidazole (MISO) is a 2-nitroimidazole with an oxygen-like effect. Clinical testing of this drug was mostly disappointing with the exception of a limited gain in small subpopulations of patients with head and neck cancer. The neurotoxicity of the drug limits its use in optimum dosage. It is also possible that the high glutathione level in certain human tumour cells may lower the sensitization efficiency. Etanidazole is another 2-nitroimidazole with a lower neurotoxicity than MISO and is currently tested at about a 3-fold the total dose of MISO. Pimonidazole is another 2-nitroimidazole with a basic side-chain which permits a high tumour concentration. Central neurotoxicity is the limiting toxic effect. The drug is particularly efficient in sensitizing human cell lines rich in glutathione. 7. 2-Nitroimidazoles have also a direct cytotoxic effect on hypoxic cells presumably due to their nitroreductive products. These products can also reduce the cellular glutathione content and enhance the cytotoxicity of alkylating and redox active chemotherapeutic agents. So far, this chemosensi- tization could not be effectively exploited in cancer treatment. 8. Reduction in tumour cell oxygenation can be accomplished by: (a) the use of agents that increase the affinity of Hb to oxygen, or (b) agents that reduce the tumour blood flow e.g. vasodilators. This may increase tumour cell death due to hypoxia, enhance the cytotoxicity of alkylating agents and may also augment the cytotoxicity of nitroimidazoles due to enhancement of formation of nitroreductive products. Manipulation of oxygen delivery to tumours for a therapeutic advantage is worth clinical testing.