Hyperthermia is a possible approach for cancer therapy. However, a major technical problem associated with the use of hyperthermia is the difficulty of heating the local tumor region to the intended temperature without damaging normal tissue. Accordingly, in hyperthermia treatment, the expression of heat shock proteins (HSPs) has been considered a complicating factor because the expression of HSPs protects cells from apoptotic cell death. In cancer immunity, on the other hand, HSPs, including HSP70, have been shown to play an important role in immune reactions. If HSP expression induced by hyperthermia is involved in tumor immunity, novel cancer immunotherapy based on hyperthermia treatment can be developed. In such a strategy, a tumor-specific hyperthermia system that can induce necrotic cell death via HSP expression without damaging non-cancerous tissues would be highly advantageous. An intracellular hyperthermia system using functionalized magnetite nanoparticles, including magnetite cationic liposomes and antibody-conjugated magnetoliposomes, facilitates tumor-specific hyperthermia; this can induce necrotic cell death via HSP expression, which in turn induces antitumor immunity. We term this novel cancer therapy as “heat immunotherapy.” This review discusses recent progress in cancer immunology via HSP expression and novel immunotherapy based on hyperthermia.
Hyperthermia has been used as one of the efficacious cancer therapies. To develop more efficient regimens for various malignant tumors, the attention has focused on searching for substances to sensitize cell lethality of tumors by hyperthermia. Inhibitors which interfere with anti-apoptosis and/or cellular proliferation signal transductions are good candidates for enhancers of heat sensitivity of cancer cells. This review summarizes signal transductions for anti-apoptosis and/or cellular proliferation after heating and inhibitors targeting key factors in these signaling transductions. The attractive sensitizers described here might contribute to high curative efficiency in hyperthermic cancer therapy.
Heat shock proteins (HSPs) are intracellular chaperone, some of which function as immune adjuvants as well as danger signals for immune system when released into extracellular milieu. These HSPs, along with their client polypeptides, are specifically bound by receptors on antigen presenting cells (APCs). This leads to APC differentiation along with delivery of the chaperoned peptides for cross-presentation to T cells. HSP-APC interactions occur through several receptors that mediate endocytosis or signal transduction. Most importantly, HSP associated antigens are forced to enter the cross-presentation pathway by APCs, resulting in CD8+ T cell activation. These unique features of HSPs for the generation of immune response will be discussed.
Background: Critical hyperthermia targets in cancer cells have to be clearly identified. Method: To determine if the DNA double strand break (DSB)-recognizing proteins, phospho-Nbs1 and Mre11, co-localize with phospho-H2AX (γH2AX), immunohistochemical methods were used with multiple antibodies. After a heat treatment at 45.5°C for 20 min, human normal fibroblasts were analyzed with a laser scanning confocal microscope at 0.5 h and 8 h post-heat treatment. Results: At 0.5 h after a heat treatment, γH2AX formed foci in the nucleus, but phospho-Nbs1 and Mre11 were scattered over the nucleus and cytoplasm, and did not co-localize with γH2AX. At 8 h after a heat-treatment, and also after X-irradiation, both phospho-Nbs1 and Mre11 co-localized with γH2AX foci, which were already present, in the nucleus. Moreover, both phospho-Nbs1 and Mre11 which were observed at 0.5 h after a heat treatment in the cytoplasm, were no longer observed in the cytoplasm at 8 h after a heat treatment. Conclusion: These findings provide support for the concept that heat, like X-rays, may lead to the induction of DSBs.
Vitamin K is a fat-soluble vitamin involved in clotting factors of blood coagulation system. Recently, various studies about bone metabolism and anti-cancer effect in vitamin K have been reported. The aim of this study was to examine the synergy effect of vitamin K3 (MK0) on the cytotoxicity of anticancer drugs with different pharmacological actions such as campthotecin (CPT), cisplatinum (CDDP), Taxol, 5-FU and VP-16. The synergism of MK0 with anti-cancer drugs in HCT116 cells was evaluated by MTT assay and by analysis with the method of Chou and Talalay. The combination of CPT with MK0 revealed a highly synergistic effect in HCT116 cells. A partial synergism was observed in the combination of 5-FU or CDDP with MK0. In contrast, the combination of MK0 with Taxol or VP-16 resulted in antagonism. Further, 24-h exposure of HCT116 cells to 10 μM of MK0 and 10 nM CPT was associated with an increased proportion of cells in S phase, and this combination of drugs promoted arrest in S and/or G2 + M phase, resulting in the enhancement of cytotoxicity of CPT by MK0. In addition, this synergism was taken place at the early phase after the treatment of both drugs by time-lapse microscopic analysis. These findings raised the possibility that the chemotherapy of MK0 with topoisomerase I poison may be useful for the improvement of patients with malignancy in clinic.
Background: Scalp angiosarcoma is an aggressive tumor characterized by a rapid and fatal course. The overall prognosis of scalp angiosarcomas is poor. Recently, paclitaxel was found to be useful for scalp and facial angiosarcomas. Methods: We conducted a retrospective review of paclitaxel in the treatment of scalp angiosarcoma patients who were admitted to the Veterans General Hospital, Taipei from 1996 to 2005 (10 years). Of these patients, 4 initially received paclitaxel and radiotherapy (1 patient underwent surgery in addition to this treatment), and 6 patients underwent either surgery alone or surgery combined with radiotherapy. Disease-free interval and overall survival duration were calculated. Statistic analyses were carried out using Student's t-test. Results: The disease-free interval was significantly prolonged in patients who received paclitaxel in the initial treatment protocol (17.8 vs. 5.7 months, p = 0.016). The overall survival duration was also prolonged in these patients; however, the difference was not significant (26.5 vs. 11.1 months, p = 0.075). The prognosis was poor in the case of disease recurrence or metastases. Conclusions: Although it was difficult to completely eliminate selection bias in this retrospective review due to the limited number of cases, paclitaxel as an initial treatment regimen for primary scalp angiosarcoma after surgery or radiotherapy appeared to prolong the disease-free interval and improve patients' quality of life.