がんの科学と治療

Cancer cells employ a deregulated cellular metabolism to leverage survival and growth advantages. The unique tumor energy metabolism presents itself as a promising target for chemotherapy. A pool of tumor energy metabolism targeting agents has been developed after several decades of efforts. This review will cover glucose and fatty acid metabolism, PI3K/AKT/mTOR, HIF-1 and glutamine pathways in tumor energy metabolism, and how they are being exploited for treatments and therapies by promising pre-clinical or clinical drugs being developed or investigated. Additionally, acidification of the tumor extracellular microenvironment is hypothesized to be the result of active tumor metabolism. This implies that tumor extracellular pH (pHe) can be a biomarker for assessing the efficacy of therapies that target tumor metabolism. Several translational molecular imaging methods (PET, MRI) for interrogating tumor acidification and its suppression are discussed as well.

Dendritic cell (DC)-based tumor vaccination holds great potential and is intensively being studied in cancer immunotherapy. Although DC vaccination can result in a survival advantage as shown in various cancer types, there is still room for improvement. Therefore, current DC vaccines urge rigorous optimization in order to increase their immune stimulating capacities for induction of antitumor immunity. In this context, strategies where the interleukin (IL) 15 transpresentation mechanism is incorporated, appear to be of great value due to the activating potential of IL-15 towards IL-15Rβγ expressing cells, such as cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. In the past 5 years, our research group designed different strategies to generate IL-15-expressing DC with superior T cell and NK cell-activating properties. In this review, we briefly describe the design of our latest DC vaccine, in which DC are genetically engineered to transpresent IL-15 via mRNA electroporation and discuss the capacity of this newly designed DC vaccine to activate NK cells and CTLs. Overall, IL-15 transpresenting DC show the potential to activate antitumor immunity and are promising candidates for DC based cancer immunotherapy.

Aim: Carcinoma of Uterine cervix is the commonest cancer affecting females in developing countries. Concurrent chemoradiation has remained the sole definitive treatment available in the advanced stages. The study was planned to take the advantage of radiosensitisation accruing due to chemotherapy at the time of brachytherapy, when approximately forty percent of total tumor dose is applied.
Materials and methods: 64 patients were enrolled who had locally advanced uterine cervix carcinoma (FIGO stage IIB to IVA) from July 2011 to May 2013 for concurrent chemotherapy and intracavitory brachytherapy after completion of concurrent chemotherapy and external beam radiotherapy followed by 3 insertion of brachytherapy separated by a week by Flexitron brachytherapy unit to point A, for each application was 6 Gy by HDR. Cisplatin was given (35 mg/m2) one day before brachytherapy in each application.
Results: At medium follow-up of 19 months (range 8 to 30 months) clinical complete response rate was found to be 89% at 3 months of follow up. Acute side effect as nausea and vomiting grade I and II were recorded as 55% and 28% respectively, no renal dysfunction and no thrombocytopenia were encountered. No patients had grade IV or life threatening toxicity. Overall survival and disease free survival after 30 months of follow up is 88% and 75% respectively.
Conclusion: Use of concurrent chemotherapy with brachytherapy is effective and feasible with acceptable toxicity for locally advanced carcinoma of the uterine Cervix.

Background: Lung cancer is one of the most lethal and common cancers in the world, causing up to 3 million deaths annually. The chemotherapeutic drugs that have been used in treating lung cancer include cisplatinpemetrexed, cisplastin-gencitabinoe, carboplatin-paclitaxel and crizotinib. Arsenic trioxide (ATO) has been used in the treatment of acute promyelocytic leukemia. However, its effects on lung cancer are not known. We hypothesize that ATO may also have a bioactivity against lung cancer, and its mechanisms of action may involve apoptosis, DNA damage and changes in stress-related proteins in lung cancer cells
Methods: To test the above stated hypothesis, lung carcinoma (A549) cells were used as the test model. The effects of ATO were examined by performing 6-diamidine-2 phenylindole (DAPI) nuclear staining for morphological characterization of apoptosis, flow cytometry analysis for early apoptosis, and western blot analysis for stressrelated proteins (Hsp70 and cfos) and apoptotic protein expressions. Also, the single cell gel electrophoresis (Comet) assay was used to evaluate the genotoxic effect.
Results: ATO-induced apoptosis was evidenced by chromatin condensation and formation of apoptotic bodies as revealed by DAPI nuclear staining. Cell shrinkage and membrane blebbing were observed at 4 and 6 μg/ml of ATO. Data from the western blot analysis revealed a significant dose-dependent increase (p < 0.05) in the Hsp 70, caspase 3 and p53 protein expression, and a significant (p < 0.05) decrease in the cfos, and bcl-2 protein expression at 4 and 6 μg/ml of ATO. There was a slight decrease in cytochrome c protein expression at 4 and 6 μg/ ml of ATO. Comet assay data revealed significant dose-dependent increases in the percentages of DNA damage, Comet tail lengths, and Comet tail moment.
Conclusion: Taken together our results indicate that ATO is cytotoxic to lung cancer cells and its bioactivity is associated with oxidative damage, changes in cellular morphology, and apoptosis.