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Malignant pleural mesothelioma (MPM) is a rare and highly aggressive neoplasm that arises from the pleural, pericardial, or peritoneal lining. Although surgery, chemotherapy, radiotherapy, and combinations of these therapies are used to treat MPM, the median survival of such patients is dismal. Therefore, there is a compelling need to develop novel therapeutics with different modes of action. Ganglioside GM2 is a glycolipid that has been shown to be overexpressed in various types of cancer. However, there are no published reports regarding the use of GM2 as a potential therapeutic target in cases of MPM. In this study, we evaluated the efficacy of the anti-GM2 antibody BIW-8962 as an anti-MPM therapeutic using in vitro and in vivo assays. Consequently, the GM2 expression in the MPM cell lines was confirmed using flow cytometry. In addition, eight of 11 cell lines were GM2-positive (73%), although the GM2 expression was variable. BIW-8962 showed a significant antibody-dependent cellular cytotoxicity activity against the GM2-expressing MPM cell line MSTO-211H, the effect of which depended on the antibody concentration and effector/target ratio. In an in vivo orthotropic mouse model using MSTO-211H cells, BIW-8962 significantly decreased the incidence and size of tumors. Additionally, the GM2 expression was confirmed in the MPM clinical specimens. Fifty-eight percent of the MPM tumors were positive for GM2, with individual variation in the intensity and frequency of staining. These data suggest that anti-GM2 antibodies may become a therapeutic option for MPM patients. In this study, the anti-GM2 antibody BIW-8962 first showed a significant ADCC activity against malignant pleural mesothelioma (MPM) cell line and therapeutic activity in an in vivo orthotropic mouse model using the cell line. Additionally, the GM2 expression was confirmed in the MPM clinical specimens. These data suggest that anti-GM2 antibodies may become a therapeutic option for MPM patients. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

We explored biomarkers suitable for monitoring sub-chronic kidney injury using the three rat models of cisplatin (CDDP)-induced kidney injury, which were designed to extend the current knowledge beyond the sub-acute exposure period. In the pilot study, a single intravenous administration of 1.5 mg kg(-1) CDDP to rats was confirmed to result in no histopathological changes. Subsequently, CDDP was intravenously administered to rats at a dose of 1.5 mg kg(-1) for 4 days at 24-h intervals (Experimental model 1) and for up to 10 weeks at weekly intervals (Experimental models 2 and 3), and the changes in blood and urine components, such as recently recommended urinary biomarkers (Kim-1, clusterin and so on) and traditional blood biomarkers (blood urea nitrogen and serum creatinine), were examined together with the histopathological changes in renal tissues during the development of the kidney injury in each model. In these experimental models, a significant increase in urinary Kim-1 was observed prior to the histopathological changes in renal tissues, and these changes were retained after the adverse histopathological changes. Significant changes in all of the other urinary biomarkers examined occurred along with the histopathological changes. In addition, the increase in urinary Kim-1 after weekly treatment with CDDP for 4 weeks was reduced in a time-dependent manner after cessation of the drug. The present findings indicate that urinary Kim-1 is the most useful biomarker for CDDP-induced rat sub-chronic kidney injury among the biomarkers examined.

Granulocyte colony-stimulating factor (G-CSF) is known to mobilize stem cells to various organs and that it participates in tissue regeneration. Effect of the recombinant human G-CSF nartograstim (CAS 134088-74-7) was tested on elastase-induced emphysema. Porcine pancreas elastase (PPE) was administered intratracheally to male Sprague-Dawley rats to induce parenchymal destruction which was assessed by measuring the mean linear intercept (Lm) in tissue sections as an indicator of air space size. Lung alveoli were destructed and Lm value was significantly increased 2 weeks after PPE instillation. Increase in Lm was sustained for 8 weeks after PPE instillation. Two weeks after PPE instillation, 100 and 200 microg/kg of G-CSF injected for 5 d, followed by once and 3 injections a week for 5 weeks had reversed the increase in Lm by 28.7% (P = 0.02) and 35.2% (P = 0.004), respectively. Coadministration of 100 microg/kg x 5 injection of G-CSF with all-trans-retinoic acid (ATRA; 3 mg/ kg/d) for 3 weeks from 2 weeks after PPE instillation significantly inhibited the increase in Lm by 36% (p < 0.01), whereas administration of G-CSF or ATRA alone did not produce significant improvement. Preventive administration of G-CSF, which was treated for 4 weeks from 4 days after PPE instillation, did not improve enlargement of Lm. These data indicate that the administration of G-CSF is beneficial for the recovery of destructed alveoli.

Adenosine shows protective effects against cellular damage and dysfunction under several adverse conditions such as inflammation and ischemia. In the current study, we examined the effects of 3-[1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1,3 )-quinazolinedione hydrochloride (KF24345), an adenosine uptake inhibitor, on cerulein-induced acute pancreatitis in mice to investigate whether inhibition of adenosine uptake could ameliorate the severity of acute pancreatitis.Acute pancreatitis was induced in mice with six intraperitoneal injections of cerulein (50 microg/kg each) at hourly intervals.The cerulein injection increased activities of serum amylase and lipase and caused pathologic changes such as interstitial edema, polymorphonuclear cell infiltration, and acinar cell necrosis in the pancreas. KF24345 (10 mg/kg p.o.) ameliorated all these changes observed in mice with acute pancreatitis, and the suppressing effect of KF24345 on the elevation in serum amylase activity was abolished by the treatment with 8-(p-sulfophenyl)theophylline, an adenosine receptor antagonist. In addition, 2-(aminocarbonyl)- -(4-amino-2,6-dichlorophenyl)-4-[5,5-bis-(4-fluorophenyl)pentyl]-1-piperazineacetamide (R75231) and dipyridamole, other adenosine uptake inhibitors, also decreased the elevated serum amylase activity.These are the first demonstrations that the adenosine uptake inhibitors ameliorate cerulein-induced acute pancreatitis in mice, and these data suggest that adenosine uptake inhibition could ameliorate the severity of acute pancreatitis in vivo.

Adenosine protects against cellular damage and dysfunction under several adverse conditions including inflammation and ischemia. In this study, we examined the effects of 3-[1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1 H ,3 H )-quinazolinedione hydrochloride (KF24345), an adenosine uptake inhibitor, on experimental acute pancreatitis induced by choline-deficient and ethionine-supplemented diet in mice. KF24345, administered with the diet onset and every 24 h thereafter, prevented hyperamylasemia, acinar cell injury and serum tumor necrosis factor-α elevation and ultimately decreased mortality. Therapeutic treatment with KF24345, which started 32 h after the diet onset, also decreased mortality. The beneficial effect of KF24345 on mortality was abolished by the pretreatment with 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3- a ][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385), a selective adenosine A 2A receptor antagonist. An intravenous injection of KF24345 at 48 h after the diet onset increased plasma adenosine concentrations in mice with acute pancreatitis. These results suggest that KF24345 shows anti-pancreatitis effects via endogenous adenosine and adenosine A 2A receptors. The adenosine uptake inhibition could be a new therapeutic approach for acute pancreatitis.