A novel polyethylene glycol (PEG)-drug conjugate of Venetoclax, a Bcl-2 inhibitor, for treatment of acute myeloid leukemia (AML)

Background: Venetoclax (VTX) is an anticancer drug. It is a selective Bcl-2 inhibitor that is clinically used for the treatment of patients with lymphomas and leukemias. Treatment with VTX, however, is accompanied by severe adverse events such as tumor lysis syndrome and neutropenia, because VTX readily binds to serum proteins, which results in poor pharmacokinetics and poor tumor tissue concentration. To avoid such adverse events, VTX is administered using a daily or weekly ramp-up schedule that is cumbersome in clinical situations. Aims: To overcome these shortcomings, we prepared a novel polyethylene glycol (PEG)-drug conjugate of VTX (PEG-VTX) and evaluated its cytotoxic effects on acute myeloid leukemia (AML) both in vitro and in vivo. Methods and results: VTX and 4-armed PEG derivatives were covalently attached through an amide bond linker. In a series of in vitro studies, PEG-VTX selectively induced potent growth inhibition of MV4-11 human AML cells via the inducement of Bcl-2-mediated apoptosis. PEG-VTX had the effect of free VTX, presumably due to the protease-mediated release of VTX from the conjugates. In in vivo studies with AML tumor-xenograft mice models, intravenous PEG-VTX promoted sufficient tumor growth suppression. Compared with a regimen of oral free VTX, the intravenous regimen in those studies used a VTX dosage that was 15–30 times smaller for an OCI-AML-2 xenograft model and a dosing regimen that was less frequent for an MV4-11 xenograft model. The most important development, however, was the absence of weight loss related to severe side effects throughout the treatments. An increase in water solubility and the resultant hydrodynamic size of VTX via PEGylation improved the pharmacokinetics of VTX by avoiding protein interactions and lessening the extravasation from blood. The result was an increase in tumor accumulation and a decrease in the nonspecific distribution of VTX. Conclusion: The results of this study suggest that PEG-VTX could be an alternative therapeutic option for the safe and effective treatment of patients with AML

Comparative Study between Nude Mice and Immunosuppressed Hamsters as Recipients of Human Tumor Xenografts

We comparatively examined nude mice and hamsters as to their suitability as recipients of human cancers. CD-1 nude mice and golden hamsters immunosuppressed with anti-hamster thymocyte serum were used. Nude mice were superior in the areas of primary transplantation and subsequent transfer and maintenance. However, growth of tumors transplantable to both animals (a lung cancer line LC-1, a colon cancer line RPMI4788) tends to be better in hamsters than in nude mice. The better development of LC-1 and RPMI4 788 cells in hamsters than in nude mice appears to be related to the superior gain in body weight shown by hamsters

FTY720 Reduces Lipid Accumulation by Upregulating ABCA1 through Liver X Receptor and Sphingosine Kinase 2 Signaling in Macrophages

Formation of foam cells as a result of excess lipid accumulation by macrophages is a pathological hallmark of atherosclerosis. Fingolimod (FTY720) is an immunosuppressive agent used in clinical settings for the treatment of multiple sclerosis and has been reported to inhibit atherosclerotic plaque development. However, little is known about the effect of FTY720 on lipid accumulation leading to foam cell formation. In this study, we investigated the effects of FTY720 on lipid accumulation in murine macrophages. FTY720 treatment reduced lipid droplet formation and increased the expression of ATP-binding cassette transporter A1 (ABCA1) in J774 mouse macrophages. FTY720 also enhanced the expression of liver X receptor (LXR) target genes such as FASN, APOE, and ABCG1. In addition, FTY720-induced upregulation of ABCA1 was abolished by knockdown of sphingosine kinase 2 (SphK2) expression. Furthermore, we found that FTY720 treatment induced histone H3 lysine 9 (H3K9) acetylation, which was lost in SphK2-knockdown cells. Taken together, FTY720 induces ABCA1 expression through SphK2-mediated acetylation of H3K9 and suppresses lipid accumulation in macrophages, which provides novel insights into the mechanisms of action of FTY720 on atherosclerosis

Adjuvant Antitumor Immunity Contributes to the Overall Antitumor Effect of Pegylated Liposomal Doxorubicin (Doxil®) in C26 Tumor-Bearing Immunocompetent Mice

Doxorubicin (DXR) has been reported to have direct cytotoxicity against cancer cells and indirect immunotoxicity by modulation of host antitumor immunity. Hence, it may prevent cancer progression by a dual mechanism. Doxil®, a formulation of DXR encapsulated in polyethylene glycol modified (PEGylated) liposomes, is the most widely used of the clinically approved liposomal anticancer drugs. However, the effect of Doxil® on host antitumor immunity is not well understood. In this study, Doxil® efficiently suppressed tumor growth in immunocompetent mice bearing C26 murine colorectal carcinomas, but not in T cell-deficient nude mice, indicating a contribution of T cells to the overall antitumor effect of Doxil®. In immunocompetent mice, Doxil® increased major histocompatibility complex (MHC-1) levels in C26 tumors, which may be an indicator of increased immunogenicity of tumor cells, and potentially amplified tumor immunogenicity by decreasing immunosuppressive cells such as regulatory T cells, tumor-associated microphages and myeloid-derived suppressor cells that collectively suppress T cell-mediated antitumor responses. This suggests that encapsulation of DXR into PEGylated liposomes increased the therapeutic efficacy of DXR though effects on host antitumor immunogenicity in addition to direct cytotoxic effects on tumor cells. This report describes the role of host antitumor immunity in the overall therapeutic effects of Doxil®. Manipulating pharmacokinetics and biodistribution of chemotherapeutic agents with immunomodulatory properties may increase their therapeutic efficacies by amplifying host antitumor immunity in addition to direct cytotoxic effects on tumor cells

Efficient construction of the hexacyclic ring core of palau'amine : the pKa concept for proceeding with unfavorable equilibrium reactions

Palau'amine has received a great deal of attention as an attractive synthetic target due to its intriguing molecular architecture and significant immunosuppressive activity, and we achieved its total synthesis in 2015. However, the synthesized palau'amine has not been readily applicable to the mechanistic study of immunosuppressive activity, because it requires 45 longest linear steps from a commercially available compound. Here, we report the short-step construction of the ABCDEF hexacyclic ring core of palau'amine. The construction of the CDE tricyclic ring core in a single step is achieved by our pKa concept for proceeding with unfavorable equilibrium reactions, and a palau'amine analog without the aminomethyl and chloride groups is synthesized in 20 longest linear steps from the same starting material. The palau'amine analog is confirmed to retain the immunosuppressive activity. The present synthetic approach for a palau'amine analog has the potential for use in the development of palau'amine probes for mechanistic elucidation

A novel intraperitoneal therapy for gastric cancer with DFP‐10825, a unique RNAi therapeutic targeting thymidylate synthase, in a peritoneally disseminated xenograft model

Purpose: In advanced gastric cancer, peritoneal dissemination is a life‐threatening mode of metastasis. Since the treatment options with conventional chemotherapy remain limited, any novel therapeutic strategy that could control such metastasis would improve the outcome of treatment. We recently developed a unique RNA interference therapeutic regimen (DFP‐10825) consisting of short hairpin RNA against thymidylate synthase (TS shRNA) and cationic liposomes. The treatment with DFP‐10825 has shown remarkable antitumor activity in peritoneally disseminated human ovarian cancer–bearing mice via intraperitoneal administration. In this study, we expanded DFP‐10825 to the treatment of peritoneally disseminated gastric cancer. Methods: DFP‐10825 was administered intraperitoneally into mice with intraperitoneally implanted human gastric cancer cells (MKN45 or NCI‐N87). Antitumor activity and host survival benefits were monitored. Intraperitoneal distribution of fluorescence‐labeled DFP‐10825 was monitored in this MKN45 peritoneally disseminated mouse model. Results: Intraperitoneal injection of DFP‐10825 suppressed tumor growth in two peritoneally disseminated cancer models (MKN45 and NCI‐N87) and increased the survival time of the MKN45 model without severe side effects. Throughout the treatment regimen, no significant body weight loss was associated with the administration of DFP‐10825. Interestingly, after intraperitoneal injection, fluorescence‐labeled DFP‐10825 retained for more than 72 hours in the peritoneal cavity and selectively accumulated in disseminated tumors. Conclusions: Intraperitoneal injection of DFP‐10825 demonstrated effective antitumor activity without systemic severe adverse effects via the selective delivery of RNAi molecules into disseminated tumors in the peritoneal cavity. Our current study indicates that DFP‐10825 could become an alternative option to improve the outcomes of patients with peritoneally disseminated gastric cancer

A Unique Gene-Silencing Approach, Using an Intelligent RNA Expression Device (iRed), Results in Minimal Immune Stimulation When Given by Local Intrapleural Injection in Malignant Pleural Mesothelioma

Background: We have recently introduced an intelligent RNA expression device (iRed), comprising the minimum essential components needed to transcribe short hairpin RNA (shRNA) in cells. Use of iRed efficiently produced shRNA molecules after transfection into cells and alleviated the innate immune stimulation following intravenous injection. Methods: To study the usefulness of iRed for local injection, the engineered iRed encoding luciferase shRNA (Luc iRed), complexed with cationic liposomes (Luc iRed/liposome-complexes), was intrapleurally injected into an orthotopic mesothelioma mouse model. Results: Luc iRed/liposome-complexes markedly suppressed the expression of a luciferase marker gene in pleurally disseminated mesothelioma cells. The suppressive efficiency was correlated with the expression level of shRNA within the mesothelioma cells. In addition, intrapleural injection of iRed/liposome-complexes did not induce IL-6 production in the pleural space and consequently in the blood compartment, although plasmid DNA (pDNA) or dsDNA (the natural construct for iRed) in the formulation did. Conclusion: Local delivery of iRed could augment the in vivo gene silencing effect without eliciting pronounced innate immune stimulation. Our results might hold promise for widespread utilization of iRed as an RNAi-based therapeutic for intracelial malignant cancers

ヒダリガワ タンノウショウ ニ タイシ フククウキョウカ タンノウ テキシュツジュツ オ シコウ シタ 3レイ ノ ケントウ

We experienced a series of 370 cases of laparoscopic cholecystectomy (Lap-C) between January 1992 and December 2001, of which three cases (0.8%) were left-sided gallbladder. When we perform Lap-C to left-sided gallbladder, we have to recognize the anatomical specificity of this disease, and to avoid the complication like injury of arteries or bile ducts. In this study we performed Lap-C to three cases of left-sided gallbladder. In all cases, the gallbladder bed were located at the left side of the hepatic round ligament, and the cystic duct were connected to normal position of the common bile duct. And in all cases, there were no anomalies of the intrahepatic portal vein. One of these cases, falling of the hepatic round ligament was seen, then we tried to insert a trocar at the left side of the ligament and to pick up it by silk. Then we could get a good view and easily performed Lap-C. In all cases we could underwent Lap-C without complication. We considered that Lap-C was to be a standard operation method for malformation cases like a left-sided gallbladder

スイトウブ スイカンナイ ニュウトウ シュヨウ ニ タイシ スイトウ ジュウニシチョウ ダイ2ブ セツジョジュツ オ オコナッタ 1レイ

We report a case of IPMT (intraductal papillary-mucinous tumor) that was performed pancreatic head resection with segmental duodenectomy. A 42-year-old man was admitted to our hospital because he was pointed out a cystic tumor of the pancreas head by near doctor. Abdominal ultrasonography and intra ductal ultrasonography showed a multiple cystic tumor with hypertrophied septum. But there were no elevated tumors in the cystic mass. MRCP showed a racemose multiple cystic tumor. ERCP showed a big orifice of papilla Vater and mucinous discharge. Based on these various examinations a diagnosis IPMT was determined. Because of no elevated tumor in the cystic mass, we suspected it was adenoma or hyperplasia. Then we determined to perform a minimal invasive operation, and underwent pancreatic head resection with segmental duodenectomy. After the operation there were no stasis of stomach and no weight loss. To determine the surgical procedure of benign IPMT, we should try to preserve the organ function. It was considered that this procedure was a useful method for benign IPMT of the pancreas head

キュウセイ タンノウエン デ ハッショウシ ジュツゼン ニ DIC トナッタ タンノウセン ヘンペイ ジョウヒガン ノ 1レイ

We report a case of resected adonosquamous carcinoma of the gallbladder with acute cholecystitis and preoperative DIC. A 79-year-old woman was admitted to our hospital because of acute cholecystitis due to cystic duct obstruction by carcinoma of the gallbladder. There were high fever and henns ‘egg-sized tumor with severe tenderness on the right hypochondrium. Based on various examinations, a diagnosis advanced crcinoma of the gallbladder (Hinf3) was determined. Until the operation, because of exacerbation of acute cholecystitis, DIC occurred. The day before operation, percutaneus transhepatic gallbladder drainage was done. Then partial liver segmentectomy (S4a and S5) with cholecystectomy was carried out. Direct infiltration to the liver was observed. Histopathologically, the gallbladder tumor was adenosquamous carcinoma. After the operation, she recovered from DIC. But metastatic lymphnodes around common bile duct were enlarged rapidly, and obstructive jaundice appeared. On 55th day after the operation, she died because of peritonitis carcinomatosa 55 postoperative days. It was considered that preoperative acute cholecystitis, DIC and postoperative obstructive jaundice resulted from rapid growth of adenosquamous carcinoma