Ketamine promotes breast tumor growth in a mouse breast tumor model involving with high expression of miR-27b-3p and EGFR
This study aimed to investigate the influence of ketamine addiction in breast tumors and related gene expressions. The effect o f ketamine treatment on proliferation, colony formation, migration, and invasion of triple-negative breast cancer cell line EO771 was examined. In addition, a ketamine addiction mice model was established by intraperitoneal injection (IP) of ketamine in mice and used to investigate the effects of ke tamine addiction on tumor growth and the possible mechanisms. In the in vitro studies, ketamine treatment at different concentrations did not affect EO771 cell proliferation and colony formation. But k...
Source: Investigational New Drugs - August 9, 2022 Category: Drugs & Pharmacology Source Type: research
Phase I study of envafolimab (KN035), a novel subcutaneous single-domain anti-PD-L1 monoclonal antibody, in Japanese patients with advanced solid tumors
AbstractEnvafolimab is the first and only globally approved subcutaneously injectable PD-L1 antibody. This open-label, multicenter Phase 1 trial assessed the safety, tolerability, pharmacokinetic (PK) profile, and efficacy of envafolimab as a single agent in Japanese patients with advanced solid tumors. In the dose-escalation phase, 10 patients received subcutaneous (SC) envafolimab QW at 1.0 mg/kg, 2.5 mg/kg and 5.0 mg/kg. In the dose-expansion phase, 16 patients were treated at 2.5 or 5.0 mg/kg Q2W in part-1 and 9 patients received SC envafolimab 300 mg Q4W in part-2. No dose-limiting toxicities (DLTs) were reporte...
Source: Investigational New Drugs - August 6, 2022 Category: Drugs & Pharmacology Source Type: research
An open-label, crossover study to compare different formulations and evaluate effect of food on pharmacokinetics of pimitespib in patients with advanced solid tumors
This study compared the bioavailability of two pimitespib formulations (Formulations A and B), evaluated the food effect on Formulation A, and evaluated the safety and efficacy of multiple pimitespib doses in patients with solid tumors. This clinical, pharmacological multicenter study had two cohorts and periods. A single dose of Formulation A or B was administered in a crossover design to compare the pharmacokinetics in Cohort 1. In Cohort 2, the effects of fed vs fasting conditions were evaluated among those receiving Formulation A. Subsequently, multiple Formulation A doses were administered to all patients for safety a...
Source: Investigational New Drugs - August 6, 2022 Category: Drugs & Pharmacology Source Type: research
Phase 1 study to evaluate the effects of rifampin on pharmacokinetics of pevonedistat, a NEDD8-activating enzyme inhibitor in patients with advanced solid tumors
SummaryPevonedistat (TAK-924/MLN4924) is an investigational small molecule inhibitor of the NEDD8-activating enzyme that has demonstrated clinical activity across solid tumors and hematological malignancies. Here we report the results of a phase 1 study evaluating the effect of rifampin, a strong CYP3A inducer, on the pharmacokinetics (PK) of pevonedistat in patients with advanced solid tumors (NCT03486314). Patients received a single 50 mg/m2 pevonedistat dose via a 1-h infusion on Days 1 (in the absence of rifampin) and 10 (in the presence of rifampin), and daily oral dosing of rifampin 600 mg on Days 3–11. Twenty ...
Source: Investigational New Drugs - August 6, 2022 Category: Drugs & Pharmacology Source Type: research
Integrated strategy of network analysis prediction and experimental validation to elucidate the possible mechanism of compound Turkish gall ointment in treating eczema
Compound Turkish gall ointment (CTGO) has a long history of being widely used as a folk medicine in Xinjiang for the treatment of eczema. CTGO is currently in the pre-investigational new drug application stage... (Source: Chinese Medicine)
Source: Chinese Medicine - July 30, 2022 Category: Complementary Medicine Authors: Xuan Ma, Meng Hao, Ming Hui Zhang, Ya Zeng, Qing Qing Yang, Lu Zhao, Chen Yang Fan, Zhi Hong Ji, Ke Ao Li, Zhi Jian Li, Mirzat Maimaiti and Ji Hong Nie Tags: Research Source Type: research
Transplanted organoids empower human preclinical assessment of drug candidate for the clinic
Sci Adv. 2022 Jul 8;8(27):eabj5633. doi: 10.1126/sciadv.abj5633. Epub 2022 Jul 6.ABSTRACTPharmacodynamic (PD) studies are an essential component of preclinical drug discovery. Current approaches for PD studies, including the analysis of novel kidney disease targeting therapeutic agents, are limited to animal models with unclear translatability to the human condition. To address this challenge, we developed a novel approach for PD studies using transplanted, perfused human kidney organoids. We performed pharmacokinetic (PK) studies with GFB-887, an investigational new drug now in phase 2 trials. Orally dosed GFB-887 to athy...
Source: Adv Data - July 20, 2022 Category: Epidemiology Authors: Amy D Westerling-Bui Eva Maria Fast Thomas W Soare Srinivasan Venkatachalan Michael DeRan Alyssa B Fanelli Sergii Kyrychenko Hien Hoang Grinal M Corriea Wei Zhang Maolin Yu Matthew Daniels Goran Malojcic Xin-Ru Pan-Zhou Mark W Ledeboer Jean-Christophe Har Source Type: research
Selinexor synergizes with azacitidine to eliminate myelodysplastic syndrome cells through p53 nuclear accumulation
AbstractMyelodysplastic syndromes (MDS) are clonal malignancies of multipotent hematopoietic stem cells, characterized by ineffective hematopoiesis leading to cytopenia. Hypomethylating agents, including azacitidine, have been used for treating MDS with some success; however, the overall survival rate remains poor and, therefore, finding new therapies is necessary. Selinexor, which exerts anticancer effects against some hematologic tumors, is a nuclear export protein inhibitor that blocks cell proliferation and induces apoptosis in various cancer cell lines. We investigated the effects of combined selinexor and azacitidine...
Source: Investigational New Drugs - July 16, 2022 Category: Drugs & Pharmacology Source Type: research
A phase Ib dose escalation study of oral monotherapy with KX2-391 in elderly patients with acute myeloid leukemia
SummaryPoor tolerance to standard therapies and multi-drug resistance complicate treatment of elderly patients with acute myeloid leukemia (AML). It is therefore imperative to explore novel tolerable agents and target alternative pathways. KX2-391 is an oral non-ATP-competitive inhibitor of Src kinase and tubulin polymerization. This multi-center phase Ib open-label safety and activity study involved elderly patients with relapsed or refractory AML, or who declined standard chemotherapy. Twenty-four patients averaging 74 years of age were enrolled. The majority previously received hypomethylating agents. Five doses were ...
Source: Investigational New Drugs - July 16, 2022 Category: Drugs & Pharmacology Source Type: research
Improved delivery of Mcl-1 and survivin siRNA combination in breast cancer cells with additive siRNA complexes
This study aimed at investigating the influence of commercial transfection reagents (Prime-Fect, Leu-Fect A, and Leu-Fect C) complexed with different siRNAs (CDC20, HSP90, Mcl-1 and Survivin) in MDA-MB-436 breast cancer cells and the impact of incorporating an anionic additive, Trans-Booster, into siRNA formulations for improving in vitro gene silencing and delivery efficiency. Gene silencing was quantitatively analyzed by real-time RT-PCR while cell proliferation and siRNA uptake were evaluated by the MTT assay and flow cytometry, respectively. Amongst the investigated siRNAs and transfection reagents, Mcl-1/Prime-Fect co...
Source: Investigational New Drugs - July 14, 2022 Category: Drugs & Pharmacology Source Type: research
Real-world data on efficacy and safety of azacitidine therapy in chronic myelomonocytic leukemia in China: results from a multicenter, retrospective study
This study provides valuable real-life data in China on the treatment schedules, efficacy and safety of AZA in the treatment of CMML. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 14, 2022 Category: Drugs & Pharmacology Source Type: research
Antitumor activity of mianserin (a tetracyclic antidepressant) primarily driven by the inhibition of SLC1A5-mediated glutamine transport
SummaryTargeting tumor metabolic vulnerabilities such as “glutamine addiction” has become an attractive approach for the discovery of novel antitumor agents. Among various mechanisms explored, SLC1A5, a membrane transporter that plays an important role in glutamine cellular uptake, represents a viable target to interfere with tumor’s ability to acqu ire critical nutrients during proliferation. In the present study, a stably transfected HEK293 cell line with human SLC1A5 (HEK293-SLC1A5) was established for the screening and identification of small molecule SLC1A5 inhibitors. This in vitro system, in conjunction with d...
Source: Investigational New Drugs - July 14, 2022 Category: Drugs & Pharmacology Source Type: research
First-in-human study of IM156, a novel potent biguanide oxidative phosphorylation (OXPHOS) inhibitor, in patients with advanced solid tumors
AbstractPreclinical models suggest anticancer activity of IM156, a novel biguanide mitochondrial protein complex 1 inhibitor of oxidative phosphorylation (OXPHOS). This first-in-human dose-escalation study enrolled patients with refractory advanced solid tumors to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Eligible patients received oral IM156 every other day (QOD) or daily (QD) and were assessed for safety, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary signals of efficacy. 22 patients with advanced cancers (gastric, n = 8; colorectal, n = 3; ovarian, n =...
Source: Investigational New Drugs - July 8, 2022 Category: Drugs & Pharmacology Source Type: research
Brain pharmacokinetics and metabolism of the AMP-activated protein kinase selective inhibitor SBI-0206965, an investigational agent for the treatment of glioblastoma
Conclusion. SBI-0206965 has adequate brain permeability but low relative oral bioavailability which may be due to rapid hepatic metabolism, likely catalyzed by CYP3A enzymes. Our observations will facilitate further development of SBI-0206965, and/or other structurally related molecules, for the treatment of GBM and other brain tumors. (Source: Investigational New Drugs)
Source: Investigational New Drugs - July 8, 2022 Category: Drugs & Pharmacology Source Type: research
3D cell cultures, as a surrogate for animal models, enhance the diagnostic value of preclinical in vitro investigations by adding information on the tumour microenvironment: a comparative study of new dual-mode HDAC inhibitors
AbstractAnchorage-independent 3D-cultures of multicellular tumour spheroids (MCTS) and in vitro microtumours of cancer cells can provide upfront information on the effects of anticancer drug candidates, tantamount to that obtained from animal xenograft studies. Unlike 2D cancer cell cultures, 3D-models take into account the influence of the tumour microenvironment and the location dependence of drug effects and accumulation. We exemplified this by comparison of the effects of two new dual-mode anticancer agents, Troxbam and Troxham, and their monomodal congeners SAHA (suberoylanilide hydroxamic acid) and CA-4 (combretastat...
Source: Investigational New Drugs - July 7, 2022 Category: Drugs & Pharmacology Source Type: research
Two novel piperidones induce apoptosis and antiproliferative effects on human prostate and lymphoma cancer cell lines
SummaryCancer remains the second most common cause of death in the US. Due to a recurrent problem with anticancer drug resistance, there is a current need for anticancer drugs with distinct modes of action for combination drug therapy We have tested two novel piperidone compounds, named 2608 (1-dichloroacetyl − 3,5-bis(3,4-difluorobenzylidene)-4-piperidone) and 2610 (1-dichloroacetyl-3,5-bis(3,4-dichlorobenzylidene)-4-piperidone), for their potential cytotoxicity on numerous human cancer cell lines. We found that both compounds were cytotoxic for breast, pancreatic, leukemia, lymphoma, colon, and fib roblast cell lines...
Source: Investigational New Drugs - July 6, 2022 Category: Drugs & Pharmacology Source Type: research
