In many past clinical studies in which hyperthermia enhanced the efficacy of radiotherapy, the tumor temperatures could be raised only to 40-42 degrees C range in most cases. The heat-induced cell death, cellular radiosensitization, and vascular damage induced by such mild temperature hyperthermia (MTH) are likely to be insignificant despite the increased response of tumors to radiotherapy. Heating rodent tumors at 40-42 degrees C was found to cause an enduring increase in blood flow and oxygenation in the tumors. Recent studies with canine soft tissue sarcoma and human tumor clinical studies also demonstrated that MTH improves tumor oxygenation, and enhances response of the tumors to radiotherapy or chemoradiotherapy. The increased blood flow and vascular permeability caused by MTH may also improve the delivery of various therapeutic agents such as chemotherapy drugs, immunotherapeutic agents and genetic constructs for gene therapy to tumor cells. MTH as a means to potentiate the efficacy of radiotherapy and others warrants further investigation.

Metformin, the most widely prescribed drug for treatment of type 2 diabetes, has been shown to exert significant anticancer effects. Hyperthermia has been known to kill cancer cells and enhance the efficacy of various anti-cancer drugs and radiotherapy. We investigated the combined effects of metformin and hyperthermia against MCF-7 and MDA-MB-231 human breast cancer cell, and MIA PaCa-2 human pancreatic cancer cells. Incubation of breast cancer cells with 0.5–10 mM metformin for 48 h caused significant clonogenic cell death. Culturing breast cancer cells with 30 µM metformin, clinically relevant plasma concentration of metformin, significantly reduced the survival of cancer cells. Importantly, metformin was preferentially cytotoxic to CD44high/CD24low cells of MCF-7 cells and, CD44high/CD24high cells of MIA PaCa-2 cells, which are known to be cancer stem cells (CSCs) of MCF-7 cells and MIA PaCa-2 cells, respectively. Heating at 42°C for 1 h was slightly toxic to both cancer cells and CSCs, and it markedly enhanced the efficacy of metformin to kill cancer cells and CSCs. Metformin has been reported to activate AMPK, thereby suppressing mTOR, which plays an important role for protein synthesis, cell cycle progression, and cell survival. For the first time, we show that hyperthermia activates AMPK and inactivates mTOR and its downstream effector S6K. Furthermore, hyperthermia potentiated the effect of metformin to activate AMPK and inactivate mTOR and S6K. Cell proliferation was markedly suppressed by metformin or combination of metformin and hyperthermia, which could be attributed to activation of AMPK leading to inactivation of mTOR. It is conclude that the effects of metformin against cancer cells including CSCs can be markedly enhanced by hyperthermia.

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Purpose: The purpose of the present study was to evaluate the efficacy of mild hyperthermia to potentiate the anticancer effects of h-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione) by up-regulating NAD(P)H:quinone oxidoreductase (NQO1) in cancer cells. Experimental Design: Effects of h-lapachone alone or in combination with mild heating on the clonogenic survival of FSaII fibrosarcoma cells of C3H mice and A549 human lung tumor cells in vitro was determined. Effects of heating on the NQO1 level in the cancer cells in vitro were assessed using Western blot analysis for NQO1 expression, biochemical determination of NQO1 activity, and immunofluorescence microscopy for NQO1 expression. Growth of FSaII tumors in the hind legs of C3H mice was determined after treating the host mice with i.p. injection of 45 mg/kg h-lapachone followed by heating the tumors at 42jC for 1 hour every other day for four times.

With increased use of intensity-modulated radiation therapy (IMRT) for head and neck treatment questions have arisen as to selection of an optimum treatment approach when either superficial sparing or treatment is desired. Other work has pointed out the increased superficial dose resulting from obliquity effects when multiple tangential beams are applied to head and neck treatment, as is the general case in IMRT planning. Helical tomotherapy might be expected to result in even further enhanced superficial dose compared with conventional bilateral field treatment. We have designed a typical right oropharynx target volume in an anthropomorphic head and neck phantom. Three different treatment techniques have been used to optimally treat this target, including bilateral static fields, eight-field IMRT and helical tomotherapy. The phantom was immobilized in a standard treatment position and treated on a Varian 2300cd linear accelerator and on a Hi-Art Helical Tomotherapy unit. 1 mm3 lithium-fluoride thermoluminescent dosimeters (TLDs) were placed on the surface of the phantom at a number of axial test positions. Film strips (Kodak EDR2) were either wrapped around the surface or sandwiched within the phantom. Measured doses at the surface and as a function of depth are compared with the planning system predictions for each treatment technique. The maximum surface doses on the proximal treatment side, averaged from TLDs and films, were measured to be 69-82% of the target dose with the bilateral fields yielding the lowest surface doses (69%), tomotherapy about 2% more than that (71%) and IMRT 13% more (82%). Anterior to the target volume, doses are always low for bilateral treatment. In this case the minimum anterior surface dose (chin area) was 6% of the prescription dose from that technique as compared with 26% and 35% from the IMRT and tomotherapy methods, respectively. The Eclipse and Tomotherapy planning systems both modelled deep and superficial doses well. Surface doses were better modelled by Eclipse at the test points, while the tomotherapy plans consistently overestimated the measured doses by 10% or more. Depth dose measurements, extracted from embedded films, indicated the depth of dose build-up to >99% to be the shallowest for IMRT (2-5 mm) followed by tomotherapy (5-8 mm) and bilateral fields (10-15 mm). The amount of surface dose is clearly technique dependent and should be taken into account in the planning stage.