Cyclophosphamide Pharmacogenomic Variation in Cancer Treatment and Its Effect on Bioactivation and Pharmacokinetics.

Cyclophosphamide (Cy) is a prodrug that is mainly bioactivated by cytochrome P450 (CYP) 2B6 enzyme. Several other enzymes are also involved in its bioactivation and affect its kinetics. Previous studies have shown the effect of the enzymes' genetic polymorphisms on Cy kinetics and its clinical outcome.

Impact of fludarabine and treosulfan on ovarian tumor cells and mesothelin chimeric antigen receptor T cells.

In addition to their immunosuppressive effect, cytostatics conditioning prior to adoptive therapy such as chimeric antigen receptor (CAR) T cells may play a role in debulking and remodeling the tumor microenvironment. We investigated in vitro the killing efficacy and impact of treosulfan and fludarabine on ovarian cancer cells expressing mesothelin (MSLN) and effect on MSLN-targeting CAR T cells. Treosulfan and fludarabine had a synergetic effect on killing of SKOV3 and OVCAR4 cells.

Dental pulp stem cells ameliorate D-galactose-induced cardiac ageing in rats.

Background: Ageing is a key risk factor for cardiovascular disease and is linked to several alterations in cardiac structure and function, including left ventricular hypertrophy and increased cardiomyocyte volume, as well as a decline in the number of cardiomyocytes and ventricular dysfunction, emphasizing the pathological impacts of cardiomyocyte ageing. Dental pulp stem cells (DPSCs) are promising as a cellular therapeutic source due to their minimally invasive surgical approach and remarkable proliferative ability.

Aim: This study is the first to investigate the outcomes of the systemic transplantation of DPSCs in a D-galactose (D-gal)-induced rat model of cardiac ageing.

miRNome and Proteome Profiling of Human Keratinocytes and Adipose Derived Stem Cells Proposed miRNA-Mediated Regulations of Epidermal Growth Factor and Interleukin 1-Alpha.

Wound healing is regulated by complex crosstalk between keratinocytes and other cell types, including stem cells. In this study, a 7-day direct co-culture model of human keratinocytes and adipose-derived stem cells (ADSCs) was proposed to study the interaction between the two cell types, in order to identify regulators of ADSCs differentiation toward the epidermal lineage. As major mediators of cell communication, miRNome and proteome profiles in cell lysates of cultured human keratinocytes and ADSCs were explored through experimental and computational analyses.

Non-additive effect of the DNA methylation inhibitor, 5-Aza-dC, and glass as a culture surface on osteogenic differentiation.

The clinical need for bone regenerative solutions is expanding with increasing life expectancy and escalating incidence of accidents. Several strategies are being investigated to enhance the osteogenic differentiation of stem cells. We previously reported two different approaches for this purpose, in monolayer and three-dimensional cell culture.

A Systematic Review of Keratinocyte Secretions: A Regenerative Perspective.

Cell regenerative therapy is a modern solution for difficult-to-heal wounds. Keratinocytes, the most common cell type in the skin, are difficult to obtain without the creation of another wound. Stem cell differentiation towards keratinocytes is a challenging process, and it is difficult to reproduce in chemically defined media.

Biomaterials as a Vital Frontier for Stem Cell-Based Tissue Regeneration.

Biomaterials and tissue regeneration represent two fields of intense research and rapid advancement. Their combination allowed the utilization of the different characteristics of biomaterials to enhance the expansion of stem cells or their differentiation into various lineages. Furthermore, the use of biomaterials in tissue regeneration would help in the creation of larger tissue constructs that can allow for significant clinical application.

Mesothelin-Specific CAR T Cells Target Ovarian Cancer.

New therapeutic options for patients with ovarian cancer are urgently needed. Therefore, we evaluated the efficacy of two second-generation mesothelin (MSLN)-directed CAR T cells in orthotopic mouse models of ovarian cancer. Treatment with CAR T cells expressing an MSLN CAR construct including the CD28 domain (M28z) significantly prolonged survival, but no persistent tumor control was observed.

Vitamin D levels and busulphan kinetics in patients undergoing hematopoietic stem cell transplantation, a multicenter study.

Vitamin D (Vit-D), an essential nutrient, interacts with different drugs including chemotherapeutic agents like busulphan, an alkylating agent used for conditioning prior to stem cell transplantation. The correlation between Vit-D plasma levels and busulphan clearance was investigated in an uncontrolled prospective study in patients and mice. Plasma 25(OH)D levels were measured and busulphan pharmacokinetics calculated in 81 patients.

Reduced Risk of Sinusoidal Obstruction Syndrome of the Liver after Busulfan-Cyclophosphamide Conditioning Prior to Allogeneic Hematopoietic Stem Cell Transplantation.

The aim of this study is to evaluate the incidence of sinusoidal obstruction syndrome (SOS) of the liver and the clinical outcome after hematopoietic stem cell transplantation (HSCT) based on several modifications in our protocols. We retrospectively investigated 372 patients undergoing myeloablative conditioning with oral busulfan (Bu) and cyclophosphamide before allogeneic HSCT during 1990-2015. Patients' supportive care was changed in order to reduce the regimen-related toxicities.

Pre-formulation investigations for establishing a protocol for treosulfan handling and activation.

Introduction: Treosulfan is an alkylating agent that is used for the treatment of ovarian cancer and for conditioning prior to stem cell transplantation. It is a prodrug that is activated non-enzymatically to two active epoxides.

Objectives: To optimize a protocol for both in vivo samples handling and in vitro drug preparation.

The effect of N-acetyl-l-cysteine (NAC) on liver toxicity and clinical outcome after hematopoietic stem cell transplantation.

Unlabelled: Busulphan (Bu) is a myeloablative drug used for conditioning prior to hematopoietic stem cell transplantation. Bu is predominantly metabolized through glutathione conjugation, a reaction that consumes the hepatic glutathione. N-acetyl-l-cysteine (NAC) is a glutathione precursor used in the treatment of acetaminophen hepatotoxicity.

Flavin-containing monooxygenase 3 (FMO3) role in busulphan metabolic pathway.

Busulphan (Bu) is an alkylating agent used in the conditioning regimen prior to hematopoietic stem cell transplantation (HSCT). Bu is extensively metabolized in the liver via conjugations with glutathione to form the intermediate metabolite (sulfonium ion) which subsequently is degraded to tetrahydrothiophene (THT). THT was reported to be oxidized forming THT-1-oxide that is further oxidized to sulfolane and finally 3-hydroxysulfolane.

Skin regeneration in three dimensions, current status, challenges and opportunities.

Skin regeneration is a life-saving need for many patients, whom list is stretched from burn victims to motor-car accidents. Spraying cells, either keratinocytes or stem cells, were associated with variable results and, in many cases, unfavorable outcomes. As the spatial configuration of the skin is distinctive, many trials investigated the bio-printing or the construction of three dimensional skin models where different layers of the skin were preserved.

Biodistribution of biodegradable polymeric nano-carriers loaded with busulphan and designed for multimodal imaging.

Background: Multifunctional nanocarriers for controlled drug delivery, imaging of disease development and follow-up of treatment efficacy are promising novel tools for disease diagnosis and treatment. In the current investigation, we present a multifunctional theranostic nanocarrier system for anticancer drug delivery and molecular imaging. Superparamagnetic iron oxide nanoparticles (SPIONs) as an MRI contrast agent and busulphan as a model for lipophilic antineoplastic drugs were encapsulated into poly (ethylene glycol)-co-poly (caprolactone) (PEG-PCL) micelles via the emulsion-evaporation method, and PEG-PCL was labelled with VivoTag 680XL fluorochrome for in vivo fluorescence imaging.

Cytochrome P450 Oxidoreductase Influences CYP2B6 Activity in Cyclophosphamide Bioactivation.

Introduction: Cyclophosphamide is commonly used as an important component in conditioning prior to hematopoietic stem cell transplantation, a curative treatment for several hematological diseases. Cyclophosphamide is a prodrug activated mainly by cytochrome P450 2B6 (CYP2B6) in the liver. A high degree of inter- and intra-individual variation in cyclophosphamide kinetics has been reported in several studies.

Cytochrome P450 2J2, a new key enzyme in cyclophosphamide bioactivation and a potential biomarker for hematological malignancies.

The role of cytochrome P450 2J2 (CYP2J2) in cyclophosphamide (Cy) bioactivation was investigated in patients, cells and microsomes. Gene expression analysis showed that CYP2J2 mRNA expression was significantly (P<0.01) higher in 20 patients with hematological malignancies compared with healthy controls.

Posaconazole concentrations in human tissues after allogeneic stem cell transplantation.

Few data have been published regarding posaconazole tissue concentrations in humans. We analyzed tissue concentrations in biopsy specimens taken at autopsy from seven patients who received posaconazole prophylaxis because of graft-versus-host disease. The results were compared to plasma concentrations collected before death.

Biodegradable polymeric vesicles containing magnetic nanoparticles, quantum dots and anticancer drugs for drug delivery and imaging.

We have developed biodegradable polymeric vesicles as a nanocarrier system for multimodal bio-imaging and anticancer drug delivery. The poly(lactic-co-glycolic acid) (PLGA) vesicles were fabricated by encapsulating inorganic imaging agents of superparamagnetic iron oxide nanoparticles (SPION), manganese-doped zinc sulfide (Mn:ZnS) quantum dots (QDs) and the anticancer drug busulfan into PLGA nanoparticles via an emulsion-evaporation method. T2∗-weighted magnetic resonance imaging (MRI) of PLGA-SPION-Mn:ZnS phantoms exhibited enhanced negative contrast with r2∗ relaxivity of approximately 523 s(-1) mM(-1) Fe.

Cyclophosphamide alters the gene expression profile in patients treated with high doses prior to stem cell transplantation.

Background: Hematopoietic stem cell transplantation is a curative treatment for several haematological malignancies. However, treatment related morbidity and mortality still is a limiting factor. Cyclophosphamide is widely used in condition regimens either in combination with other chemotherapy or with total body irradiation.

Comparison of algorithms for oral busulphan area under the concentration-time curve limited sampling estimate.

Background And Objectives: Therapeutic drug monitoring (TDM) of the first dose of busulphan during conditioning prior to allogeneic stem cell transplantation provides the possibility of improving the clinical outcome via dose adjustment of subsequent doses. The plasma area under the concentration-time curve (AUC) for busulphan is generally accepted as the parameter that gives the best exposure estimate; however, the sampling frequency needed for reliable AUC calculation remains controversial. The aim of the present investigation was to develop and evaluate a limited sampling model for oral busulphan.

Pharmacokinetics and biodistribution of the cyclin-dependent kinase inhibitor -CR8- in mice.

Background: CR8 is a second generation inhibitor of cyclin-dependent kinases derived from roscovitine. CR8 was shown to be 50-100 fold more potent than roscovitine in inducing apoptosis in different tumor cell lines. In the present investigation, we have established an analytical method for the quantification of CR8 in biological samples and evaluated its bioavailability, biodistribution and pharmacokinetics in mice.

Gas chromatographic-mass spectrometry method for the detection of busulphan and its metabolites in plasma and urine.

Busulphan is an alkylating agent used as conditioning regimen prior to stem cell transplantation. Busulphan is metabolized in the liver and four major metabolites have been identified. The first metabolite is tetrahydrothiophene which is oxidized to tetrahydrothiophene 1-oxide, then sulfolane and finally 3-hydroxy sulfolane.