The overall objective of this research program is the development of hyperthermia for the treatment of human cancer. At the present time the ability to controllably elevate local tumor temperatures is a major impediment in clinical applications. Here we present approaches toward improved clinical systems. To better understand how such systems should be applied in the future, basic biological investigations into the mechanisms associated with heat killing and potentiation of other anticancer treatments are also put forward. Proposed is the development of a processing field magnetic induction system for the treatment of bulky deep seated human neoplasms including intrathoracic tumors. This system offers a number of significant advantages over existing systems as well as a number of drawbacks, particularly unwanted power deposition in normal tissues surrounding tumors. The development of this system is a test of the hypothesis that processing magnetic fields can be exploited to substantially improve hyperthermia for large and deep seated tumors. This will be accomplished by reducing the presently limiting toxicities associated with unwanted power deposition in normal issues and improving the specific absorption rate (SAR) in tumors. Interstitial radiation therapy, brachytherapy, is the treatment of choice for a variety of human neoplasms and is ideally suited to combination with hyperthermia. In addition data presented in the progress report section demonstrated a cohort of difficult to heat, probably highly perfused, human tumors. To address this area, we propose the development of An """"""""N"""""""" electrode interstitial hyperthermia system for tumors in the head and neck, thorax, pelvis/perineum, and central nervous system. To advance our understanding of how best to apply hyperthermia to the cancer problem, we also propose biological investigations to elucidate the mechanism of hyperthermic cell killing, protection from and sensitization to heat insult and the potentiation of other agents, e.g ionizing radiation and chemotherapeutic drugs. Central to this line of investigation is the hypothesis that protein influx to the nucleus after heat insult is primarily a cytotoxic rather than cytoprotective event. We believe that this increase in nuclear affinic proteins (NAP) becomes cytotoxic by inhibiting, among other things, DNA transcription and replication and by the suppression of repair of damage caused by other agents. A comprehensive model is presented in an attempt to unify a large body of literature dealing with thermal biology. It centers around cytoplasmic release of the NAP under stress (e.g. heat) and the specific binding of these proteins to nuclear matrix binding sites (NMBS). After the stress or threat to the cell is removed the heat stress proteins (HSP) then remove the NAP and resequester them in cytoplasm. While the model is imperfect it offers explanations for such diverse phenomena as thermal tolerance (TT) and heat potentiation of radiation and drugs and we have used it to develop a comprehensive laboratory test of the hypothesis.
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