Reductive Metabolism Influences the Toxicity and Pharmacokinetics of the Hypoxia-Targeted Benzotriazine Di-Oxide Anticancer Agent SN30000 in Mice.

3-(3-Morpholinopropyl)-7,8-dihydro-6-indeno[5,6-][1,2,4]triazine 1,4-dioxide (SN30- 000), an analog of the well-studied bioreductive prodrug tirapazamine (TPZ), has improved activity against hypoxic cells in tumor xenografts. However, little is known about its biotransformation in normal tissues. Here, we evaluate implications of biotransformation of SN30000 for its toxicokinetics in NIH-III mice.

Development and validation of a LC-MS/MS method for the quantification of the checkpoint kinase 1 inhibitor SRA737 in human plasma.

Aim: SRA737 is an orally active small-molecule inhibitor of checkpoint kinase 1 being investigated in an oncology setting. A HPLC-MS/MS method for quantifying plasma concentrations of SRA737 was validated.

Methods & Results: Sample preparation involved protein precipitation with acetonitrile following addition of CN-deuterated SRA737 as internal standard.

The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity.

The primary aim of this clinical trial was to determine the feasibility of delivering first-generation CAR T cell therapy to patients with advanced, CEACAM5 malignancy. Secondary aims were to assess clinical efficacy, immune effector function and optimal dose of CAR T cells. Three cohorts of patients received increasing doses of CEACAM5-specific CAR T cells after fludarabine pre-conditioning plus systemic IL2 support post T cell infusion.

Anti-Folate Receptor-α IgE but not IgG Recruits Macrophages to Attack Tumors via TNFα/MCP-1 Signaling.

IgE antibodies are key mediators of antiparasitic immune responses, but their potential for cancer treatment via antibody-dependent cell-mediated cytotoxicity (ADCC) has been little studied. Recently, tumor antigen-specific IgEs were reported to restrict cancer cell growth by engaging high-affinity Fc receptors on monocytes and macrophages; however, the underlying therapeutic mechanisms were undefined and proof of concept was limited. Here, an immunocompetent rat model was designed to recapitulate the human IgE-Fcε receptor system for cancer studies.

Pregnane X Receptor (PXR)-Mediated Gene Repression and Cross-Talk of PXR with Other Nuclear Receptors via Coactivator Interactions.

Pregnane X receptor is a ligand-activated nuclear receptor (NR) that mainly controls inducible expression of xenobiotics handling genes including biotransformation enzymes and drug transporters. Nowadays it is clear that PXR is also involved in regulation of intermediate metabolism through -activation and -repression of genes controlling glucose, lipid, cholesterol, bile acid, and bilirubin homeostasis. In these processes PXR cross-talks with other NRs.

A phase I/II trial of AT9283, a selective inhibitor of aurora kinase in children with relapsed or refractory acute leukemia: challenges to run early phase clinical trials for children with leukemia.

Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints.

Development of downstream processing to minimize beta-glucan impurities in GMP-manufactured therapeutic antibodies.

The presence of impurities or contaminants in biological products such as monoclonal antibodies (mAb) could affect efficacy or cause adverse reactions in patients. ICH guidelines (Q6A and Q6B) are in place to regulate the level of impurities within clinical drug products. An impurity less often reported and, therefore, lacking regulatory guideline is beta-glucan.

Beta-glucan contamination of pharmaceutical products: How much should we accept?

Beta-glucans are large polysaccharides produced by a range of prokaryotic and eukaryotic organisms. They have potential immunostimulatory properties and have been used with therapeutic intent as anti-microbial and anti-tumour agents. A range of other potentially beneficial effects have been described, and oral forms of beta-glucans are widely available over-the-counter and online.

Trends in the characteristics, dose-limiting toxicities and efficacy of phase I oncology trials: The Cancer Research UK experience.

Introduction: Phase I oncology trials have evolved over the years, and these changes could have implications for future studies and patients.

Methods: Adult trials sponsored by Cancer Research UK Centre for Drug Development between 1995 and 2013 were analysed. Forty-nine trials were divided into two groups based on the starting date for recruitment: 1995-2003 (24 trials, n = 603) and 2004-2013 (25 trials, n = 750) for comparative purposes.

2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents.

Increasing prevalence of hypertension (HTN) in children and adolescents has become a significant public health issue driving a considerable amount of research. Aspects discussed in this document include advances in the definition of HTN in 16 year or older, clinical significance of isolated systolic HTN in youth, the importance of out of office and central blood pressure measurement, new risk factors for HTN, methods to assess vascular phenotypes, clustering of cardiovascular risk factors and treatment strategies among others. The recommendations of the present document synthesize a considerable amount of scientific data and clinical experience and represent the best clinical wisdom upon which physicians, nurses and families should base their decisions.

A Cancer Research UK First Time in Human Phase I Trial of IMA950 (Novel Multipeptide Therapeutic Vaccine) in Patients with Newly Diagnosed Glioblastoma.

Purpose: To perform a two-cohort, phase I safety and immunogenicity study of IMA950 in addition to standard chemoradiotherapy and adjuvant temozolomide in patients with newly diagnosed glioblastoma. IMA950 is a novel glioblastoma-specific therapeutic vaccine containing 11 tumor-associated peptides (TUMAP), identified on human leukocyte antigen (HLA) surface receptors in primary human glioblastoma tissue.

Experimental Design: Patients were HLA-A*02-positive and had undergone tumor resection.

Targeting Carcinoembryonic Antigen with DNA Vaccination: On-Target Adverse Events Link with Immunologic and Clinical Outcomes.

Purpose: We have clinically evaluated a DNA fusion vaccine to target the HLA-A*0201-binding peptide CAP-1 from carcinoembryonic antigen (CEA) linked to an immunostimulatory domain (DOM) from fragment C of tetanus toxin.

Experimental Design: Twenty-seven patients with CEA-expressing carcinomas were recruited: 15 patients with measurable disease (arm-I) and 12 patients without radiological evidence of disease (arm-II). Six intramuscular vaccinations of naked DNA (1 mg/dose) were administered up to week 12.

Cancer Research UK Centre for Drug Development: translating 21st-century science into the cancer medicines of tomorrow.

The Cancer Research UK Centre (CRUK) for Drug Development (CDD) can trace its origins back to the Cancer Research Campaign Phase I/II Committee (created in 1980) and to date has tested over 120 potential cancer medicines in early-phase clinical trials. Five drugs are now registered, providing benefit to thousands of patients with cancer as part of their routine standard of care. In recent years, the CDD has established several different business and operating models that provide it with access to the pipelines of pharmaceutical and biotechnology companies.

Can formulation and drug delivery reduce attrition during drug discovery and development-review of feasibility, benefits and challenges.

Drug discovery and development has become longer and costlier process. The fear of failure and stringent regulatory review process is driving pharmaceutical companies towards "me too" drugs and improved generics (505(b) (2)) fillings. The discontinuance of molecules at late stage clinical trials is common these years.

Improved oral delivery of resveratrol using proliposomal formulation: investigation of various factors contributing to prolonged absorption of unmetabolized resveratrol.

Objectives: The objective of this study was to design lipid-based formulation to enhance the absorption of unmetabolized resveratrol (RSV) over adequate time and investigate various factors that contribute to prolonged absorption of RSV.

Methods: Proliposomal formulations containing distearoyl phosphatidyl choline (DSPC) with or without cholesterol were prepared and evaluated. The liposomes obtained from hydration of proliposomal mixture were evaluated for size, zeta, physical appearance and entrapment.

Nuclear receptors in regulation of biotransformation enzymes and drug transporters in the placental barrier.

Over the past 20 years, the toxicological and protective roles of the placental barrier with respect to drug detoxification and transporter-controlled protection of the fetus have been intensively examined. Several cytochrome P450 enzymes are expressed in placental trophoblast at different stages of pregnancy, though only a few of these have functional activity to metabolize xenobiotics. Drug transporters such as P-glycoprotein/MDR1 or breast cancer resistance protein (BCRP) are highly expressed in the placenta, and their functional activities have been demonstrated in the placenta both in vitro and in vivo.