While hyperthermia (HT) is a promising modality for cancer therapy, major difficulty with the use of HT is the development of thermotolerance due to the elevation of heat shock proteins (HSPs), which function as molecular chaperons. Among the HSPs, Hsp70 possesses cytoprotective activity and plays a critical role in the acquisition of thermotolerance. Upon heat stress, Hsp70 rapidly translocates from the cytoplasm to nucleus. Recently, the protein Hikeshi, also known as the gene product of C11orf73, has been shown to function as a nuclear import carrier of Hsp70 under heat-stress conditions. Knockdown of Hikeshi significantly enhances sensitivity to HT and mild HT in the presence-but not the absence-of heat-stress in human cancer cells. Moreover, upregulation of Hikeshi expression is observed in human gastric or renal cancer. It has also been suggested that functional defects leading to homozygosity for a missense mutation, p. Cys4Ser or p. Val54Leu, in Hikeshi cause leukoencephalopathy in Finnish or Ashkenazi-Jewish patients, respectively.

This review summarizes the physiological and pathological roles of Hikeshi and discusses its potential as a target in HT therapy.

Solid cancer therapy based on necrosis induction with heat-generating nanoparticles has been developed in Japan. Heat was induced from intratumorally injected magnetite cationic lipid composite particles (MCL particles) by alternating magnetic field irradiations to kill cancer cells nearby located. In our previous report we have showed importance of heat dose index in vivo (J/cm3 tumor volume) for tumor regression when 45 mg MCL particles were injected at a single site of 1.36 cm3 tumor. Purpose of this study is to show rationale and utility of multiple site injections of MCL particles for treatment of large tumors more than 1.36 cm3.

Rat mammary tumors were induced by 7,12-dimethylbenz［a］anthracene (DMBA) and tumors in range of 2.19 ～ 3.81 cm3 were applied to treatment experiment. Treatment condition was designed to reproduce the heat generation condition of the 1.36 cm3 tumor treatment at every multiple injection site in rat mammary tumors. Tumor volume divided by number of injection sites (cm3/site) was set to close to 1.36 cm3/site and 45 mg MCL particles were administered at multiple sites to keep even spaces among injection sites. Three irradiation conditions were set to give close heat dose in vivo (J/cm3) of the 1.36 cm3 tumor treatment. Treatment under designed conditions resulted in complete regression of rat tumors at 21 days after the treatment, showing theoretical validity of design procedures for the multiple site injections. Novel concept of necrosed tumor volume from an injection site (cm3/site) and its actual value under a standard injection condition of 45 mg-MCL/site were described and its use in clinic was discussed.