FUTURE-DIRECTIONS IN HYPERTHERMIA BIOLOGY

Eric Hall pointed out many years ago that in hyperthermia the biology is with us, but the physics is against us. Over the years the basic truth in that statement has not wavered. Our best evidence suggests that temperature distributions are 1-1.5-degrees-C too low, on average. However, investigations in biology may lead to sensitization of tumours to hyperthermia, even with the temperatures that are already achievable in the clinic. Biologists are now starting to realize that more studies need to be done in the temperature range between 37 and 42-degrees-C, since this is the range that is most often reached in the clinic. For example, Dr Hahn coined the term hyperthermic sensitizer for those drugs that are not cytotoxic at 37-degrees-C, but have observable cytotoxicity at elevated temperatures. A new class of hyperthermic sensitizers, azo-dihydrochlorides, decompose in aqueous media to release free radicals. Almost no cytotoxicity of these drugs is observed at 37-degrees-C, but the drugs are exquisitely cytotoxic at temperatures of 41-42-degrees-C. Identification of additional compounds with such properties is warranted, since systemic cytotoxicity could be avoided. Hahn also suggested that the increase in blood flow that occurs in tumours during heating could be exploited as a means to increase drug delivery. Use of this approach to enhance delivery of monoclonal antibodies has proven fruitful. Since long duration heating combined with low dose-rate irradiation leads to obliteration of the radiation dose-rate effect, this approach may be particularly advantageous with monoclonal antibodies radiolabelled with low LET isotopes. Microcarrier systems, such as liposomes could also benefit from the increased tumour blood flow that occurs during hyperthermia, particularly if the lipid is temperature sensitive, so that the contents are released in the region where the heat is applied. Another biologic strategy to enhance the therapeutic effects of hyperthermia is to lower pH. Hahn and Shiu demonstrated several years ago that the heat-sensitizing effect of this strategy only occurs if the cells are acutely exposed to low pH. The most exciting recent work in this area has been in the use of ionophores. Manipulation of blood flow could be used to increase temperatures during hyperthermia.