Pharmacokinetic study of adriamycin in the emulsion mixed with lipiodol-difference resulting from composition and methods of preparation, and behavior after mesenteric arterial injection in rat]

We experimentally investigated the pharmacokinetics of adriamycin (ADM) in a similar of transcatheter arterial chemoembolization therapy (TAE) of hepatocellular carcinoma using emulsion of lipiodol (Lp) mixed with ADM followed by gelatin sponge, and the difference resulting from composition and method of preparation of the emulsion as well as behavior after mesenteric arterial injection in rat. In in vitro study, the emulsion with iopamidol (iopamiron 300 : IP) was more stable than with amidotrizoic acid (60% Urografin : UG). The highest stability was found in the mixing ratio of Lp. IP and distilled water at 1 : 0.42 : 0.08. Frequent pumping also made the emulsion more stable. But in optimally composed emulsion, pumping 20 or 50 times made no difference in the stability during 30 min. which may be longer than the time from preparation to injection time of the emulsion in clinical application. After injection of the emulsion into the mesenteric artery which may simulate injection into the hepatic artery in hepatocellular carcinoma, the arterial blood flow was suspended. In the peripheral arteries the emulsion separated into two phases of Lp and ADM solution, forming striped pattern, and Lp embolization of the peripheral artery persisted for over 45 min. while ADM extravasated. These findings suggest that after Lp-TAE, Lp maintains an embolizing effect while ADM penetrates into the surrounding tumor tissue, and that this is an underlying mechanism for the anti-cancer effect of Lp-TAE.     

Effects of thermal stimulation, applied to the hindpaw via a hot water bath, upon ovarian blood flow in anesthetized nonpregnant rats

The effects of thermal stimulation, applied to the hindpaw via a hot bath set to either 40 degrees C (non-noxious) or 49 degrees C (noxious), upon ovarian blood flow were examined in nonpregnant anesthetized rats. Ovarian blood flow was measured using a laser Doppler flowmeter. Blood pressure was markedly increased following 49 degrees C stimulation. Ovarian blood flow, however, showed no obvious change during stimulation, although a small increase was observed after stimulation. Ovarian blood flow and blood pressure responses to 49 degrees C stimulation were abolished after hindlimb somatic nerves proximal to the stimuli were cut. Heat stimulation (49 degrees C) resulted in remarkable increases in both ovarian blood flow and blood pressure in rats in which the sympathetic nerves supplying the ovary were cut but the hindlimb somatic nerves remained intact. The efferent activity of the ovarian plexus nerve was increased during stimulation at 49 degrees C. Stimulation at 40 degrees C had no effect upon ovarian blood flow, blood pressure or ovarian plexus nerve activity. Electrical stimulation of the distal part of the severed ovarian plexus nerve resulted in a decrease in both the diameter of ovarian arterioles, observed using a digital video microscope, and ovarian blood flow.The present results demonstrate that noxious heat, but not non-noxious warm, stimulation of the hindpaw skin in anesthetized rats influences ovarian blood flow in a manner that is attributed to reflex responses in ovarian sympathetic nerve activity and blood pressure.     

Roles for hENT1 and dCK in gemcitabine sensitivity and malignancy of meningioma

BackgroundHigh-grade meningiomas are aggressive tumors with high morbidity and mortality rates that frequently recur even after surgery and adjuvant radiotherapy. However, limited information is currently available on the biology of these tumors, and no alternative adjuvant treatment options exist. Although we previously demonstrated that high-grade meningioma cells were highly sensitive to gemcitabine in vitro and in vivo, the underlying molecular mechanisms remain unknown.MethodsWe examined the roles of hENT1 (human equilibrative nucleoside transporter 1) and dCK (deoxycytidine kinase) in the gemcitabine sensitivity and growth of meningioma cells in vitro. Tissue samples from meningiomas (26 WHO grade I and 21 WHO grade II/III meningiomas) were immunohistochemically analyzed for hENT1 and dCK as well as for Ki-67 as a marker of proliferative activity.ResultshENT1 and dCK, which play critical roles in the intracellular transport and activation of gemcitabine, respectively, were responsible for the high gemcitabine sensitivity of high-grade meningioma cells and were strongly expressed in high-grade meningiomas. hENT1 expression was required for the proliferation and survival of high-grade meningioma cells and dCK expression. Furthermore, high hENT1 and dCK expression levels correlated with stronger tumor cell proliferative activity and shorter survival in meningioma patients.ConclusionsThe present results suggest that hENT1 is a key molecular factor influencing the growth capacity and gemcitabine sensitivity of meningioma cells and also that hENT1, together with dCK, may be a viable prognostic marker for meningioma patients as well as a predictive marker of their responses to gemcitabine.     

Triton WR1339, an inhibitor of lipoprotein lipase, decreases vitamin E concentration in some tissues of rats by inhibiting its transport to liver

The aim of this experiment was to clarify the contribution of the alpha-tocopherol transfer activity of lipoprotein lipase (LPL) to vitamin E transport to tissues in vivo. We studied the effect of Triton WR1339, which prevents the catabolism of triacylglycerol-rich lipoproteins by LPL on vitamin E distribution in rats. Vitamin E-deficient rats fed a vitamin E-free diet for 4 wk were injected with Triton WR1339 and administered by oral gavage an emulsion containing 10 mg of alpha-tocopherol, 10 mg of gamma-tocopherol, or 29.5 mg of a tocotrienol mixture with 200 mg of sodium taurocholate, 200 mg of triolein, and 50 mg of albumin. alpha-Tocopherol was detected in the serum and other tissues of the vitamin E-deficient rats, but gamma-tocopherol, alpha- and gamma-tocotrienol were not detected. Triton WR1339 injection elevated (P<0.05) the serum alpha-tocopherol concentration and inhibited (P<0.05) the elevation of alpha-tocopherol concentration in the liver, adrenal gland, and spleen due to the oral administration of alpha-tocopherol. Neither alpha-tocopherol administration nor Triton WR1339 injection affected (P>or=0.05) the alpha-tocopherol concentration in the perirenal adipose tissue, epididymal fat, and soleus muscle despite a high expression of LPL in the adipose tissue and muscle. These data show that alpha-tocopherol transfer activity of LPL in adipose tissue and muscle is not important for alpha-tocopherol transport to the tissue after alpha-tocopherol intake or that the amount transferred is small relative to the tissue concentration. Furthermore, Triton WR1339 injection tended to elevate the serum gamma-tocopherol (P=0.071) and alpha-tocotrienol (P=0.053) concentrations and lowered them (P<0.05) in the liver and adrenal gland of rats administered gamma-tocopherol or alpha-tocotrienol. These data suggest that lipolysis of triacylglycerol-rich chylomicron by LPL is necessary for postprandial vitamin E transport to the liver and subsequent transport to the other tissues.     

FMS‐like tyrosine kinase 3 (FLT3) amplification in patients with metastatic colorectal cancer

FMS‐like tyrosine kinase 3 (FLT3) plays a key role in hematopoiesis. However, the oncogenic role of FLT3 amplification in patients with metastatic colorectal cancer (mCRC) remains unclear. Here, we aimed to evaluate the characteristics, prognosis, and treatment efficacy of an FLT3 inhibitor (regorafenib) in patients with mCRC with FLT3 amplifications. Tumor tissue samples from 2329 patients were sequenced using NGS in the Nationwide Cancer Genome Screening Project in Japan. The effects of clinicopathological features, co‐altered genes, prognosis, and efficacy of regorafenib were investigated. Between April 2015 and June 2018, 85 patients with mCRC with FLT3 amplification were observed. There were no differences in baseline characteristics between patients with or without FLT3 amplification. The frequency of RAS or other gene co‐alterations was inversely correlated with the copy number status. Median survival time in patients with FLT3 amplification was significantly shorter compared with those with non‐FLT3 amplification. Further investigations of FLT3 amplification as a potential treatment target in mCRC are warranted.     

Phase I study of napabucasin in combination with FOLFIRI + bevacizumab in Japanese patients with metastatic colorectal cancer

International Journal of Clinical Oncology - Napabucasin is an oral NAD(P)H:quinone oxidoreductase 1 bioactivatable agent that generates reactive oxygen species, is hypothesised to affect multiple...     

Concentrations of Organotin Compounds in Tissues and Organs of Dugongs from Thai Coastal Waters

Concentrations of butyltin (BT) and phenyltin (PT) compounds were measured in organs and tissues of dugongs (Dugong dugon) from the coastal waters of Thailand. Concentrations of BTs and PTs were in the range of 14–14,468 and <1–30 μg kg⁻¹ (detection frequency: 79%), respectively. Although concentrations of BTs in dugongs were higher then reported concentrations in cetaceans and pinnipeds, PTs were lower in dugongs. In half of the dugongs in which measurements were made, the concentration of BTs in the liver was the highest among the all the tissues and organs tested. Dibutyltin (DBT) or monobutyltin (MBT) was found to be the dominant compounds among the BTs. The distribution in the body of PTs was not clear because of the lower levels of this compound. TPT was the dominant compound among PTs. The coastal area of Thailand is located off the Gulf of Thailand and the Andaman Sea. Concentrations of organotin (OT) compounds in dugongs collected from the Gulf of Thailand were compared to those from the Andaman Sea. No significant differences in BT or PT concentrations were observed between the two areas (p < 0.05). The concentrations of BTs and PTs in the livers of dugongs were decreased between 1998 and 2002, suggesting a decrease in OT concentrations in the surrounding environment.     

Dietary sesame seed and its lignan increase both ascorbic acid concentration in some tissues and urinary excretion by stimulating biosynthesis in rats

We previously showed that the intake of sesamin, a major lignan in sesame seed, decreased lipid peroxidation and elevated tocopherol concentration in rat tissues. In this study, we examined the effect of dietary sesame seed and sesamin on the ascorbic acid concentration in rat tissues. Rats (4-wk-old) were fed either a vitamin E-free diet, or a diet containing 50 mg gamma-tocopherol/kg, one containing 2 g sesamin/kg, one containing 50 mg gamma-tocopherol/kg and 2 g sesamin/kg, or one containing 200 g sesame seed/kg for 28 d. The dietary sesamin and sesame seed elevated ascorbic acid concentrations in the liver and kidney, and increased urinary excretion in those Wistar rats. The dietary sesamin also elevated the hepatic mRNA levels of cytochrome P450 (CYP) 2B, and UDP-glucuronosyltransferase (UGT) 1A and 2B. In contrast, neither the sesamin nor the sesame seed affected the liver concentration of ascorbic acid in ODS rats with a hereditary defect in ascorbic acid synthesis, though the dietary sesame seed elevated the UGT1A and 2B mRNA levels in the liver. In addition, the sesame seed elevated the gamma-tocopherol concentration in the various ODS rat tissues and the ascorbic acid concentrations in the kidney, heart and lung, while reducing the thiobarbituric acid reactive substance concentration in the heart and kidney. These results suggest that dietary sesame seed and its lignan stimulate ascorbic acid synthesis as a result of the induction of UGT1A and the 2B-mediated metabolism of sesame lignan in rats. The data of ODS rat studies also suggest that dietary sesame seed enhances antioxidative activity in the tissues by elevating the levels of two antioxidative vitamins, vitamin C and E.