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A method of automated synthesis of [18F]fluoromisonidazole ([18F]FMISO) for application in preclinical studies on small animals was presented. A remote-controlled synthesizer Synthra RNplus was used for nucleophilic substitution of NITTP (1′-(2′-nitro-1-imidazolyl)-2-O-tetrahydropyranyl-3-O-toluenesulfonyl-propanediol) with 18F anion. Labeling of 5 mg of precursor was performed in anhydrous acetonitrile at 100°C for 10 min, and the hydrolysis with HCl was performed at 100°C for 5 min. Final purification was done with high-performance liquid chromatography (HPLC) and the radiochemical purity of radiotracer was higher than 99%. Proposed [18F]FMISO synthesis was used as a reliable tool in studies on hypoxia in Lewis lung carcinoma (LLC) in mouse models.

Hypoxia, an inevitable feature of locally advanced solid tumors, has been known as an adverse prognostic factor, a driver of an aggressive phenotype, and an unfavorable factor in therapies. Myo-inositol trispyrophosphate (ITPP) is a hemoglobin modifier known to both increase O2 release and normalize microvasculature. Our goal was to measure the tumor oxygen partial pressure dynamic changes and timing of the therapeutic window after ITPP systemic administration. Two syngeneic tumor models in mice, B16 melanoma and 4T1 breast carcinoma, were used, with varying ITPP dose schedules. Tissue oxygenation level was measured over several days in situ in live animals by Electron Paramagnetic Resonance oximetry with implanted OxyChip used as a constant sensor of the local pO2 value. Both B16 and 4T1 tumors became more normoxic after ITPP treatment, with pO2 levels elevated by 10–20 mm Hg compared to the control. The increase in pO2 was either transient or sustained, and the underlying mechanism relied on shifting hypoxic tumor areas to normoxia. The effect depended on ITPP delivery intervals regarding the tumor type and growth rate. Moreover, hypoxic tumors before treatment responded better than normoxic ones. In conclusion, the ITPP-generated oxygen therapeutic window may be valuable for anti-tumor therapies requiring oxygen, such as radio-, photo- or immunotherapy. Furthermore, such a combinatory treatment can be especially beneficial for hypoxic tumors. [ABSTRACT FROM AUTHOR]

Combinations of metabolic blockers (including fenofibrate) with chemotherapeutic drugs interfere with the drug‐resistance of prostate cancer cells. However, their effect on cancer stem cells‐dependent microevolution of prostate cancer malignancy remains unaddressed. Here, we hypothesize that the combined docetaxel/fenofibrate treatment prompts the selective expansion of cancer stem cells that affects the microevolution of their progenies. Accordingly, we adapted a combined in vitro/in vivo approach to identify biological and therapeutic consequences of this process. Minute subpopulations of docetaxel‐resistant CD133high and/or CD44high cancer stem cell‐like (SCL) cells were found in prostate cancer DU145 and PC3 cell populations. When pretreated with docetaxel, they readily differentiated into docetaxel‐resistant CD44negative "bulk" cells, thus accounting for the microevolution of drug‐resistant cell lineages. Combined docetaxel/fenofibrate treatment induced the generation of poly(morpho)nuclear giant cells and drug‐resistant CD44high SCL cells. However, the CD44negative offspring of docetaxel‐ and docetaxel/fenofibrate‐treated SCLs remained relatively sensitive to the combined treatment, while retaining enhanced resistance to docetaxel. Long‐term propagation of drug‐resistant SCL‐derived lineages in the absence of docetaxel/fenofibrate resulted in their reverse microevolution toward the drug‐sensitivity and invasive phenotype. Consequently, prostate tumors were able to recover from the combined docetaxel/fenofibrate stress after the initial arrest of their expansion in vivo. In conclusion, we have confirmed the potential of fenofibrate for the metronomic treatment of drug‐resistant prostate tumors. However, docetaxel/fenofibrate‐induced selective expansion of hyper‐resistant CD44high SCL prostate cells and their "bulk" progenies prompts the microevolution of prostate tumor drug‐resistance. This process can limit the implementation of metabolic chemotherapy in prostate cancer treatment. [ABSTRACT FROM AUTHOR]