146 research outputs found
Interleukin-3 : identification, characterization and molecular evolution
Blood contains large numbers of various cell types. The mature blood cell types
exert highly specialized functions such as oxygen and carbon dioxide transport,
blood clotting and defense against infections by antibody production, cell
mediated immunity and phagocytosis. Most of these mature blood cell types
have a limited life span and therefore need to be produced continuously. This
process of blood cell formation, termed hemopoiesis, is impressive since daily
approximately 1011 new blood cells are generated in man.
In steady state situations, the continuous replacement of terminally differentiated
cells is tuned with great precision but the hemopoietic system can respond
dramatically to environmental stress, such as bleeding or infection. The primary site of hemopoiesis is the bone marrow which permits the
formation of all blood cell types i.e., erythrocytes, platelets, monocytes,
neutrophils, basophils, eosinophils and lymphocytes. The continuous
replenishment of functionally mature hemopoietic cells ill vivo is strictly
dependent on the presence of a small but persistent pool of bone marrow
plmipotent hemopoietic stem cells.
The mechanism(s) controlling hemopoiesis appear to involve regulation
mediated by a group of interacting specific glycoproteins designated
hemopoietic growth factors. Furthermore, it has been implied that
microenvironmental stromal cells support hemopoiesis as well. Several mechanisms through which stromal cells affect
hemopoiesis have been postulated, i.e., a direct cell contact regulated mechanism, secretion of CSFs; expression of antagonists of differentiation-inducing
factor(s) and/or self-renewal mediators
Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump
Imatinib mesylate (STI571), a potent tyrosine kinase inhibitor, is
successfully used in the treatment of chronic myelogenous leukemia and
gastrointestinal stromal tumors. However, the intended chronic oral
administration of imatinib may lead to development of cellular resistance
and subsequent treatment failure. Indeed, several molecular mechanisms
leading to imatinib resistance have already been reported, including
overexpression of the MDR1/ABCB1 drug pump. We examined whether imatinib
is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug
pump that is frequently overexpressed in human tumors. Using a panel of
well-defined BCRP-overexpressing cell lines, we provide the first evidence
that imatinib is a substrate for BCRP, that it competes with mitoxantrone
for drug export, and that BCRP-mediated efflux can be reversed by the
fumitremorgin C analog Ko-143. Since BCRP is highly expressed in the
gastrointestinal tract, BCRP might not only play a role in cellular
resistance of tumor cells but also influence the gastrointestinal
absorption of imatinib
Inactivation of the Saccharomyces cerevisiae SKY1 gene induces a specific modification of the yeast anticancer drug sensitivity profile accompanied by a mutator phenotype
The therapeutic potential of the highly active anticancer agent cisplatin
is severely limited by the occurrence of cellular resistance. A better
understanding of the molecular pathways involved in cisplatin-induced cell
death could potentially indicate ways to overcome cellular
unresponsiveness to the drug and thus lead to better treatment results. We
used the budding yeast Saccharomyces cerevisiae as a model organism to
identify and characterize novel genes involved in cisplatin-induced cell
kill, and found that SKY1 (SR-protein-specific kinase from budding yeast)
is a cisplatin sensitivity gene whose disruption conferred cisplatin
resistance. In cross-resistance studies, we observed resistance of yeast
sky1 Delta cells (i.e., cells from which the SKY1 gene had been disrupted)
to cisplatin, carboplatin (but not oxaliplatin), doxorubicin and
daunorubicin, and hypersensitivity to cadmium chloride and 5-fluorouracil.
Furthermore, these cells did not display reduced platinum accumulation,
DNA platination or doxorubicin accumulation, indicating that the
resistance is unrelated to decreased drug import or increased drug export.
Based on the modification of the anticancer drug sensitivity profile and
our finding that sky1 Delta cells display a mutator phenotype, we propose
that Sky1p might play a significant role in specific repair and/or
tolerance pathways. Disruption of the S. cerevisiae SKY1 gene would thus
result in deregulation of such mechanisms and, consequently, lead to
altered drug sensitivity
SKY1 is involved in cisplatin-induced cell kill in Saccharomyces cerevisiae, and inactivation of its human homologue, SRPK1, induces cisplatin resistance in a human ovarian carcinoma cell line
The therapeutic potential of cisplatin, one of the most active and widely
used anticancer drugs, is severely limited by the occurrence of cellular
resistance. In this study, using budding yeast Saccharomyces cerevisiae as
a model organism to identify novel drug resistance genes, we found that
disruption of the yeast gene SKY1 (serine/arginine-rich protein-specific
kinase from budding yeast) by either transposon insertion or one-step gene
replacement conferred cellular resistance to cisplatin. Heterologous
expression of the human SKY1 homologue SRPK1 (serine/arginine-rich
protein-specific kinase) in SKY1 deletion mutant yeast cells restored
cisplatin sensitivity, suggesting that SRPK1 is a cisplatin sensitivity
gene, the inactivation of which could lead to cisplatin resistance.
Subsequently, we investigated the role of SRPK1 in cisplatin sensitivity
and resistance in human ovarian carcinoma A2780 cells using antisense
oligodeoxynucleotides. Treatment of A2780 cells with antisense
oligodeoxynucleotides directed against the translation initiation site of
SRPK1 led to down-regulation of SRPK1 protein and conferred a 4-fold
resistance to cisplatin. The human SRPK1 gene has not been associated with
drug resistance before. Our new findings strongly suggest that SRPK1 is
involved in cisplatin-induced cell kill and indicate that SRPK1 might
potentially be of importance for studying clinical drug resistance
RNA expression of breast cancer resistance protein, lung resistance-related protein, multidrug resistance-associated proteins 1 and 2, and multidrug resistance gene 1 in breast cancer: correlation with chemotherapeutic response
PURPOSE: The aim of this study was to investigate whether expression of
particular drug resistance genes in primary operable breast cancer
correlates with response to first-line chemotherapy in advanced disease.
EXPERIMENTAL DESIGN: We determined mRNA levels of BCRP, LRP, MRP1, MRP2,
and MDR1 in 59 primary breast tumor specimens of patients who
The PI3-kinase delta inhibitor idelalisib (GS-1101) targets integrin-mediated adhesion of chronic lymphocytic leukemia (CLL) cell to endothelial and marrow stromal cells
CLL cell trafficking between blood and tissue compartments is an integral part of the disease process. Idelalisib, a phosphoinositide 3-kinase delta (PI3K\u3b4) inhibitor causes rapid lymph node shrinkage, along with an increase in lymphocytosis, prior to inducing objective responses in CLL patients. This characteristic activity presumably is due to CLL cell redistribution from tissues into the blood, but the underlying mechanisms are not fully understood. We therefore analyzed idelalisib effects on CLL cell adhesion to endothelial and bone marrow stromal cells (EC, BMSC). We found that idelalisib inhibited CLL cell adhesion to EC and BMSC under static and shear flow conditions. TNF\u3b1-induced VCAM-1 (CD106) expression in supporting layers increased CLL cell adhesion and accentuated the inhibitory effect of idelalisib. Co-culture with EC and BMSC also protected CLL from undergoing apoptosis, and this EC- and BMSC-mediated protection was antagonized by idelalisib. Furthermore, we demonstrate that CLL cell adhesion to EC and VLA-4 (CD49d) resulted in the phosphorylation of Akt, which was sensitive to inhibition by idelalisib. These findings demonstrate that idelalisib interferes with integrin-mediated CLL cell adhesion to EC and BMSC, providing a novel mechanism to explain idelalisib-induced redistribution of CLL cells from tissues into the blood
Cytokine and angiogenic factors associated with efficacy and toxicity of pazopanib in advanced soft-tissue sarcoma: An EORTC-STBSG study
Background: Pazopanib has activity in relapsed non-adipocytic soft-tissue sarcomas (STS). A series of serum cytokines and angiogenic factors (CAFs) at baseline and changes in soluble vascular endothelial growth factor receptor-2 (sVEGFR2) or placental-derived growth factor (PlGF) levels during treatment were explored for their association with outcome.Methods:Twenty-three baseline CAFs, and sVEGFR2 and PlGF changes were measured in 85 and 32 patients, respectively. Associations between baseline CAF levels and efficacy parameters, plus between-week 12 sVEGFR2 and PlGF levels and pazopanib-specific toxicities were investigated.Results:At baseline, low interleukin (IL)-12 p40 subunit and MPC3 levels were associated with better progression-free survival (PFS) at 12 weeks (PFS 12wks), low basic nerve growth factor and hepatocyte growth factor with a better PFS, and low inter-cellular adhesion molecule-1 and IL-2 receptor alpha with prolonged overall survival (OS; all P=0.05). Pazopanib decreased sVEGFR2 and increased PlGF levels. Low sVEGFR2 and high PlGF levels at week 12 were associated with higher-grade hypertension, with TSH elevations and with poorer PFS 12wks, and OS (both P=0.05).Conclusion:Several baseline CAFs were related to outcome parameters. Low sVEGFR2 and high PlGF at week 12 associate with several pazopanib-specific toxicities and poorer efficacy. If confirmed, these factors may be used as early markers for response to and toxicity from pazopanib, enabling further individualisation of STS treatment
Optical dipole traps and atomic waveguides based on Bessel light beams
We theoretically investigate the use of Bessel light beams generated using
axicons for creating optical dipole traps for cold atoms and atomic
waveguiding. Zeroth-order Bessel beams can be used to produce highly elongated
dipole traps allowing for the study of one-dimensional trapped gases and
realization of a Tonks gas of impentrable bosons. First-order Bessel beams are
shown to be able to produce tight confined atomic waveguides over centimeter
distances.Comment: 20 pages, 5 figures, to appear in Phys. Rev.
Circadian variation in tamoxifen pharmacokinetics in mice and breast cancer patients
The anti-estrogen tamoxifen is characterized by a large variability in response, partly due to pharmacokinetic differences. We examined circadian variation in tamoxifen pharmacokinetics in mice and breast cancer patients. Pharmacokinetic analysis was performed in mice, dosed at six different times (24-h period). Tissue samples were used for mRNA expression analysis of drug-metabolizing enzymes. In patients, a cross-over study was performed. During three 24-h periods, after tamoxifen dosing at 8 a.m., 1 p.m., and 8 p.m., for at least 4 weeks, blood samples were collected for pharmacokinetic measurements. Differences in tamoxifen pharmacokinetics between administration times were assessed. The mRNA expression of drug-metabolizing enzymes showed circadian variation in mouse tissues. Tamoxifen exposure seemed to be highest after administration at midnight. In humans, marginal differences were observed in pharmacokinetic parameters between morning and evening administration. Tamoxifen Cmax and area under the curve (AUC)0–8 h were 20 % higher (P max was shorter (2.1 vs. 8.1 h; P = 0.001), indicating variation in absorption. Systemic exposure (AUC0–24 h) to endoxifen was 15 % higher (P < 0.001) following morning administration. The results suggest that dosing time is of marginal influence on tamoxifen pharmacokinetics. Our study was not designed to detect potential changes in clinical outcome or toxicity, based on a difference in the time of administration. Circadian rhythm may be one of the many determinants of the interpatient and intrapatient pharmacokinetic variability of tamoxifen
Relationship Between Sunitinib Pharmacokinetics and Administration Time: Preclinical and Clinical Evidence
Background and Objective: Circadian rhythms may influence the pharmacokinetics of drugs. This study aimed to elucidate whether the pharmacokinetics of the orally administered drug sunitinib are subject to circadian variation. Methods: We performed studies in male FVB-mice aged 8–12 weeks, treated with single-dose sunitinib at six dosing times. Plasma and tissue samples were obtained for pharmacokinetic analysis and to monitor messenger RNA (mRNA) expression of metabolizing enzymes and drug transporters. A prospective randomized crossover study was performed in which patients took sunitinib once daily at 8 a.m., 1 p.m., and 6 p.m at three subsequent courses. Patients were blindly randomized into two groups, which determined the sequence of the sunitinib dosing time. The primary endpoint in both studies was the difference in plasma area under the concentration–time curve (AUC) of sunitinib and its active metabolite SU12662 between dosing times. Results: Sunitinib and SU12662 plasma AUC in mice followed an ~12-h rhythm as a function of administration time (p ≤ 0.04). The combined AUC from time zero to 10 h (AUC10) was 14–27 % higher when sunitinib was administered at 4 a.m. and 4 p.m. than at 8 a.m. and 8 p.m. Twenty-four-hour rhythms were seen in the mRNA levels of drug transporters and metabolizing enzymes. In 12 patients, sunitinib trough concentrations (Ctrough) were higher when the drug was taken at 1 p.m. or 6 p.m. than when taken at 8 a.m. (Ctrough-1 p.m. 66.0 ng/mL; Ctrough-6 p.m. 58.9 ng/mL; Ctrough-8 a.m. 50.7 ng/mL; p = 0.006). The AUC was not significantly different between dosing times. Conclusions: Our results indicate that sunitinib pharmacokinetics follow an ~12-h rhythm in mice. In humans, morning dosing resulted in lower Ctrough values, probably resulting from differences in elimination. This can have implications fo
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