Geldanamycin and its less toxic derivative, 17-allylamino-17-demethoxygeldanamycin (17AAG), are ansamycin benzoquinone compounds, and have anti-proliferative and apoptotic activities in tumor cells. Neither drug directly binds or inhibits oncogenic kinases, but they both bind specifically to the ATP/ADP pocket of Heat shock protein 90 (Hsp90) and destabilize complexes of Hsp90 with associated proteins. The dissociation of Hsp90 from these complexes triggers the degradation of proteins involved in cellular survival, resulting in cell death. 17AAG is being developed as an anti-cancer agent, and phase I studies indicate that 17AAG has an acceptable toxicity profile. Here, we review the in vitro and in vivo studies on the role of 17AAG in treatments when used in combination with anti-cancer agents and ionizing radiation.

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Civilization-associated diseases, including cancers, are the result of cellular adaptation to microenvironments aided by the high expression of heat shock proteins (Hsps). Knowledge of tumor biology has exploded during the last few decades, and this has led to the development of target based drug discovery. These target based anticancer drugs act by blocking cell proliferation and by inducing cytostasis which is followed by the apoptosis of tumor cells. Being central regulators of cellular homeostasis, and by helping tumor cells to escape from stress induced cell death, Hsps have been recognized as pharmacological targets for anticancer treatments. Hsp inhibitors elicit their effects through the inhibition of the chaperone functions of Hsps, thus attacking multiple cellular signaling pathways. Inhibiting stress responses not only inhibits Hsp synthesis but sensitizes tumor cells to chemotherapeutic agents. Hyperthermia has been used as a treatment for several pathological states and diseases to improve recovery rates ; thus tumor cells that have defective stress responses can be sensitized to apoptosis using hyperthermia or heat shock. Selective combination of anti-Hsp drugs with hyperthermia have been shown to have the desired cytostatic/cytotoxic effects in some tumor models. A discussion of the effects of enforced apoptosis using anti-Hsp inhibitors, and facilitated apoptosis using hyperthermia, either alone or in combination, is presented.

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Currently, the molecular mechanisms involved in heat-induced cell killing are not completely understood, although protein denaturation is known to be the major target for hyperthermia in cancer cells. A new hypothesis is described here which proposes that heat-induced cell killing is associated with cellular DNA double-strand break (DSB) formation. This review provides details of this model for hyperthermia cell killing, and a possible mechanism to explain heat-induced DSB formation.

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A new high intensity focused ultrasound (HIFU) apparatus (Sonic CZ901 : Mianyang Sonic Electronic Ltd, China) was installed in our hospital last December. The device has been used 20 times in 12 advanced cancer patients, and some results concerning the use of HIFU ablation and Whole body hyperthermia (WBH) via far-infrared equipment (RHS 7500 : Enthermics Medical Systems, USA) can be reported. The first patient had pharyngeal cancer (20y.o, F) with lung and multiple liver metastases. The lung tumor shrank after WBH (weekly treatments, for a total of 4 treatments) and the liver tumor was clearly reduced by HIFU treatment. A second patient who received the combined treatment had a neck tumor with bone metastasis (65y.o, M). The patient received WBH after HIFU treatment for a 7th rib bone metastasis. After 10 days, the neck tumor developed internal necrosis, and ruptured. CT imaging showed necrotic changes focused in the neck tumor and also the rib bone metastasis.
These results may be a positive indication for HIFU treatment, but there are other positive indications for the primary organ tumor. This new thermal combination therapy appears to have great promise.

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