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.

Cellular senescence is considered as an important tumor-suppressive mechanism. Here, we demonstrated that heparan sulfate (HS) prevents cellular senescence by fine-tuning of the fibroblast growth factor receptor (FGFR) signaling pathway. We found that depletion of 3′-phosphoadenosine 5′-phosphosulfate synthetase 2 (PAPSS2), a synthetic enzyme of the sulfur donor PAPS, led to premature cell senescence in various cancer cells and in a xenograft tumor mouse model. Sodium chlorate, a metabolic inhibitor of HS sulfation also induced a cellular senescence phenotype. p53 and p21 accumulation was essential for PAPSS2-mediated cellular senescence. Such senescence phenotypes were closely correlated with cell surface HS levels in both cancer cells and human diploid fibroblasts. The determination of the activation of receptors such as FGFR1, Met, and insulin growth factor 1 receptor β indicated that the augmented FGFR1/AKT signaling was specifically involved in premature senescence in a HS-dependent manner. Thus, blockade of either FGFR1 or AKT prohibited p53 and p21 accumulation and cell fate switched from cellular senescence to apoptosis. In particular, desulfation at the 2-O position in the HS chain contributed to the premature senescence via the augmented FGFR1 signaling. Taken together, we reveal, for the first time, that the proper status of HS is essential for the prevention of cellular senescence. These observations allowed us to hypothesize that the FGF/FGFR signaling system could initiate novel tumor defenses through regulating premature senescence.

The pharmacokinetic interaction between clozapine, an atypical antipsychotic with metabolic complications, including weight gain, and green tea consumption has not been evaluated, although green tea is responsible for beneficial effects, including weight reduction, and is widely consumed in the world. Commercial green tea extract (175 mg kg(-1)) or saline was administered orally for 4 days before the oral administration of clozapine (20 mg kg(-1) ) to rats. Plasma concentrations of clozapine were measured up to 5 h after clozapine administration, and then hepatic CYP1A2 expression and activity were determined. There was no significant difference in the elimination half-life of clozapine between the green tea extract and saline groups. However, the time to reach peak concentration (T(max)) was significantly increased by green tea extract. The mean total area under the plasma concentration-time curve (AUC(0-infinity)) and maximal peak plasma concentration (C(max)) of clozapine in the green tea extract group were significantly lower than those of controls. Green tea extract induced a approximately 2-fold increase in hepatic CYP1A2 levels, while the activity increased slightly (by 10% of control). Because of this reduction in AUC and T(max) of clozapine by green tea extract pretreatment, we suggest that both the rate and amount of absorption of clozapine may be reduced by green tea extract, although the hepatic elimination phase may not be significantly altered. Therefore, the clinical implications of the effects of green tea on the bioavailability of clozapine in patients should be further evaluated.