15 Now I turn to all the advantages of heat in the ght against cancer. I alluded to these in the previous article but now I will go into some greater detail. So, what does heating actually do. Thermotherapy has been divided into three different ranges. Firstly, there is the range 38 to 40 °C which is physiological; then there is 41 to 43 °C, which is the therapeutic hyperthermic range; and lastly there is greater than 43°C which is deleterious to the body. Physiological Heat Interleukin-1 (IL-1) is produced when an infection or other immune trigger occurs. The IL-1 directly affects the brain, and a signal is sent via integratory pathways to the hypothalamus which is the heat regulatory centre. An efferent response from the hypothalamus will cause appropriate effector body organs to raise the body temperature. On tumour cells, heat in this range has a direct cytotoxic affect but with minimal growth arrest, there is an increase in vascular blood ow within the tumour and a myriad of affects occur within the immune system. These affects include cellular enhancement in that there is activation of natural cells, phagocytes and dendritic cells with cross priming of CD8 T cells and improved movement of lymphocytes. In addition, heat shock proteins undergo increased production and lastly there is an increase in cytokines, chemokines and cell adhesion molecules. Therapeutic Heat In this thermal range the cytotoxic effect is more profound and there is a linear relationship with the thermal input. There is a direct effect on mitosis because RNA and DNA synthesis is impaired and DNA repair mechanisms are curtailed. The vascular alterations allow improved oxygenation to the tumour tissue and improved drug delivery. The immune effects are the same as in the physiological range. Deleterious Heat In this range cytotoxicity is more profound and exponential. There is apoptosis and indiscriminate cell damage. The vascular changes reduce blood ow due to damage to the endothelial cells, increased wall permeability and the presence of microthrombi. The immune response wanes as heat shock proteins are reduced and all the cellular responses are damaged resulting in immunosuppression. Delving deeper into the physiology of therapeutic heat I will look at the three aspects of tumour destruction as summarised above. Direct Cytotoxicity Cytotoxicity targets mitosis and repair mechanisms. This cytotoxicity is reversed when the heat is withdrawn. A linear growth arrest occurs targeting the S phase mainly but also slowing the M phase of mitosis. The S phase suppression is due to prolonged reduction in DNA synthesis and a brief reduction in RNA synthesis. Tumour cells, which are not normal, evade apoptosis mechanisms by rapidly dividing because cell arrest mechanisms are blocked. This prevents the apoptotic mechanisms from coping efciently. The slowed mitosis allows the apoptotic pathways breathing space to perform their function optimally. Interestingly the G phase of mitosis is protected by the accumulation of heat shock proteins. The raised temperature interferes with protein repair mechanisms. Proteins are damaged by the concomitant chemotherapy, and this will amplify the chemotherapeutic effect by signicantly enhancing cell apoptosis. Improved Vascularisation Increasing the temperature of tissues leads to vasodilatation. This allows better blood ow and more of a chemotherapeutic drug will be carried to the target tissue. As tumour tissue is already well endowed with a maximised blood supply, going beyond the therapeutic range will cause normal tissue to steal blood ow from the cancerous tissue as it seeks to heal itself. A better blood ow permits increased oxygenation of cancerous tissue. Research in the last hundred years showed that solid cancers have regions of mild to severe hypoxia due to abnormal vascular function. Research started in 1909 when Dr Schwarz rst observed how changes in vascular function affected radiosensitivity of tissues. The Germans continued to dominate the research into the 1920’s when oxygen was demonstrated as pivotal for radiosensitivity and glycolysis described in tumour cells when confronted with increased oxygen levels. Cancer cells adapt by having an altered UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE
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