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Ototoxicity is a problem of special importance in children, because deafness hampers their language and psychosocial development. Intestinal tissue is embedded in cylinders of agarose before slicing. Inhalable doxorubicin might be an effective therapy in NSCLC patients with acceptable hematologic and non-hematologic toxic effects. This latter compound, in contrast to cisplatin, was not active as a mutagen. Here, we clearly identify the human organic cation transporter 2 hOCT2 as the critical transporter for cis-platin nephrotoxicity in isolated human proximal tubules and offer a potential mechanism for reducing nephrotoxicity in clinical practice. The total number, sex, and genotypes provided will vary, although typically 8 or more animals are provided.

To overcome limitations of commonly used in vitro and in vivo models, precision-cut liver slices PCLSs were used in this study. PCLSs, prepared from liver tissue obtained from male Wistar rats, were cultured in supraphysiological concentrations of glucose, fructose, insulin, and palmitic acid to mimic metabolic syndrome.

Accumulation of lipid droplets was visible and measurable after 24 h in PCLSs incubated with glucose, fructose, and insulin, both in the presence and absence of palmitic acid. Upregulation of acetyl-CoA carboxylase 1 and 2, and of sterol responsive element binding protein 1c, suggests increased de novo lipogenesis in PCLSs cultured under these conditions. Thus, steatosis was successfully induced in PCLSs with modified culture medium.

This novel ex vivo NAFLD model could be used to investigate the multicellular and molecular mechanisms that drive NAFLD development and progression, and to study potential anti-steatotic drugs. Cisplatin, or cis-diamminedichloridoplatinum II , is a ma- jor anticancer drug in the treatment of several solid tu- mors 1 2 3 4 5. Cisplatin induces cell death by binding to DNA and inhibiting replication and transcription 1.

Nov Nucleic Acids Res. Wenping Lyu Lv. Cisplatin is one of the most widely used anticancer drugs. Its efficiency is unfortunately severely hampered by resistance. Consequently, the hydrophobic anchoring of the side chain of F37 between the two cross-linked guanines at the platinated site-a key element of the complexes formation - is more stable than in the complex without PTM.

The collective behavior of multisite PTMs, as revealed here by the synchrony of contacts, may have a general significance for the modulation of intermolecular recognitions occurring in vivo. Sep The molecular mechanisms of toxicity and cellular transport of anticancer metallodrugs, including platinum-based agents, have not yet been fully elucidated.

Initially, the cytotoxic effects of both cisplatin and 1 were studied in a small panel of human cancer cells, and against a non-tumorigenic cell line in vitro. Thus, the human ovarian cancer cell line A and its cisplatin resistant variant AcisR, were selected, being most sensitive to the treatment of the gold complex. ICP-MS Inductively Coupled Plasma Mass Spectrometry analysis of the cell extracts showed that co-incubation with CuCl2 increases Au and Cu accumulation in both cancer cell lines, in accordance with the enhanced antiproliferative effects.

Conversely, for cisplatin, no increase in Pt content could be observed in both cell lines after co-incubation with either CuCl2 or cimetidine, excluding the involvement of CTR1, OCT2, and MATE in drug accumulation and overall anticancer effects. This result, together with the evidence for increased Cu content in A cells after cisplatin co-treatment with CuCl2, suggests that copper accumulation is the reason for the observed enhanced anticancer effects in this cell line.

Moreover, metal uptake studies in the same cell lines indicate that both 1 and cisplatin are not transported intracellularly by CTR1 and OCT2. DNA—affibody nanoparticle delivery system for cisplatin-based breast cancer chemotherapy. Jan Cisplatin is the most widely used anticancer drug, but its side effects limit the maximum systemic dose.

To circumvent the side effects, a DNA tetrahedron-affibody nanoparticle was prepared by combination of a DNA chain with cisplatin via interstrand crosslinks or adducts. The nano-drug inhibited the growth of BT cells by Comparison of quick recovery outcome of inhalable doxorubicin and cisplatin in lung cancer patients: May Systematic chemotherapy has required high time span for recovery in cancer patients, serious toxic effects, and increased the time of cancer-free survival of patient but decreased the overall survival time of patients irrespective of diseased condition s.

To compare the quick recovery of inhalable doxorubicin and cisplatin in the lung cancer patients. A total of patients with non-small cell lung cancer NSCLC patients were randomly divided into two groups of each. Volume, diameter, type, and a number of lung nodes, pulmonary function, and day lung cancer risk assessment were evaluated.

DON and CPN both groups had shrunken the lung cancer nodule, decreased solid nodules and non-solid nodules, and increased partially solid nodules. The DON group 5. The incidence of nodular size reduction was 9. The CPN group had Inhalable doxorubicin might be an effective therapy in NSCLC patients with acceptable hematologic and non-hematologic toxic effects.

Trial registry: An Overview. Mar Chem Eur J. At the same time, the bioconjugation of Au III complexes has emerged as a promising strategy for improving the selectivity of this class of compounds for cancer cells over healthy tissues, and recent developments have shown that combining gold complexes with molecular structures that are recognized by the cell can exploit the cell's own transport mechanisms to improve selective metal uptake.

Show more. Nat Protoc 9: Sep Nat Protocol. Precision-cut tissue slices PCTS are viable ex vivo explants of tissue with a reproducible, well defined thickness. They represent a mini-model of the organ under study and contain all cells of the tissue in their natural environment, leaving intercellular and cell-matrix interactions intact, and are therefore highly appropriate for studying multicellular processes.

PCTS are mainly used to study the metabolism and toxicity of xenobiotics, but they are suitable for many other purposes. Here we describe the protocols to prepare and incubate rat and human liver and intestinal slices. Slices are prepared from fresh liver by making a cylindrical core using a drill with a hollow bit, from which slices are cut with a specially designed tissue slicer.

Intestinal tissue is embedded in cylinders of agarose before slicing. A Comparative invitro and exvivo Study. Jul ChemMedChem. A series of organometallic Au I N-heterocyclic carbene NHC complexes was synthesized and characterized on anticancer activity in four human cancer cell lines. The compounds' toxicity in healthy tissue was determined using precision cut kidney slices PCKS as a tool to determine the potential selectivity of the Au complexes ex vivo.

All evaluated compounds presented cytotoxic activity towards the cancer cells in the nano- or low micromolar range. The mixed Au I NHC complex - ter-butylethynyl -1,3-bis- 2,6-diisopropylphenyl -imidazolylidene gold I , bearing an alkynyl moiety as ancillary ligand, showed high cytotoxicity in cancer cells in vitro, while being barely toxic in healthy rat kidney tissues.

The obtained results open new perspectives towards the design of mixed NHC-alkynyl gold complexes for cancer therapy. Aug Inorg Chem. Controlling the relative and absolute configuration of octahedral metal complexes constitutes a key challenge that needs to be overcome in order to fully exploit the structural properties of octahedral metal complexes for applications in the fields of catalysis, materials sciences, and life sciences.

Herein, we describe the application of a proline-based chiral tridentate ligand to decisively control the coordination mode of an octahedral rhodium III complex. We demonstrate the mirror-like relationship of synthesized enantiomers and differences between diastereomers. Further, we demonstrate, using the established pyridocarbazole pharmacophore ligand as part of the organometallic complexes, the importance of the relative and absolute stereochemistry at the metal toward chiral environments like protein kinases.

Protein kinase profiling and inhibition data confirm that the proline-based enantiopure rhodium III complexes, despite having all of the same constitution, differ strongly in their selectivity properties despite their unmistakably mutual origin. Moreover, two exemplary compounds have been shown to induce different toxic effects in an ex vivo rat liver model.

Gold I NHC-based homo- and heterobimetallic complexes: Synthesis, characterization and evaluation as potential anticancer agents. Jul J Biol Inorg Chem. While N-heterocyclic carbenes NHC are ubiquitous ligands in catalysis for organic or industrial syntheses, their potential to form transition metal complexes for medicinal applications has still to be exploited.

Within this frame, we synthesized new homo- and heterobimetallic complexes based on the Au I -NHC scaffold. The compounds were synthesized via a microwave-assisted method developed in our laboratories using Au I -NHC complexes carrying a pentafluorophenol ester moiety and another Au I phosphane complex or a bipyridine ligand bearing a pendant amine function. All the compounds were fully characterized by several spectroscopic techniques including far infrared, and were tested for their antiproliferative effects in a series of human cancer cells.

They showed moderate anticancer properties. Their toxic effects were also studied ex vivo using the precision-cut tissue slices PCTS technique and initial results concerning their reactivity with the seleno-enzyme thioredoxin reductase were obtained. Jul J Med Chem. Five platinum II complexes bearing a 1,3-dibenzyl imidazolylidene ligand but different leaving groups trans to it were examined for cytotoxicity, DNA and cell cycle interference, vascular disrupting properties, and nephrotoxicity.

The cytotoxicity of the complexes 3a-c increased with the steric shielding of their leaving chloride ligand, and complex 3c featuring two triphenylphosphanes was most efficacious with sub-micromolar IC50 concentrations. The complexes 3a-c interacted with DNA in electrophoretic mobility shift and ethidium bromide binding assays. The cationic complex 3c did not bind coordinatively to DNA but led to its aggregation, a damage not amenable to the usual repair mechanisms.

Complex 3c also disrupted the blood vessels in the chorioallantoic membrane of fertilized chicken eggs. Ex vivo studies using precision-cut tissue slices suggested the nephrotoxicities of 3a-c to be clinically manageable. Exploring the potential of gold III cyclometallated compounds as cytotoxic agents: The crystal structure of one compound has been solved using X-ray diffraction methods.

All compounds were tested in vitro in five human cancer cell lines including lung, breast, colon and ovarian cancer cells. For comparison purposes, all compounds were also tested in a model of human healthy cells from embryonic kidney. Notably, all new compounds were more toxic than their cyclometallated precursor bearing two chlorido ligands, and the derivative bearing one phosphane ligand presented the most promising toxicity profile in our in vitro screening, displaying a p53 dependent activity in colorectal cancer HCT cells.

We report on an improved method of synthesis of N-benzylaminoferrocene-based prodrugs and demonstrate its applicability by preparing nine new aminoferrocenes. Their effect on the viability of selected cancer cells having different p53 status was studied.

The obtained data are in agreement with the hypothesis that the toxicity of aminoferrocenes is not dependent upon p53 status. Subsequently the toxicity of a selected prodrug 4 was investigated ex vivo using rat precision cut liver slices and in vivo on hybrid male mice BDF1.

In both experiments no toxicity was observed: Finally, prodrug 4 was shown to extend the survival of BDF1 mice carrying L leukemia from Transcriptomics hit the target: Monitoring of ligand-activated and stress response pathways for chemical testing. High content omic methods provide a deep insight into cellular events occurring upon chemical exposure of a cell population or tissue.

However, this improvement in analytic precision is not yet matched by a thorough understanding of molecular mechanisms that would allow an optimal interpretation of these biological changes. For transcriptomics TCX , one type of molecular effects that can be assessed already is the modulation of the transcriptional activity of a transcription factor TF. As more ChIP-seq datasets reporting genes specifically bound by a TF become publicly available for mining, the generation of target gene lists of TFs of toxicological relevance becomes possible, based on actual protein-DNA interaction and modulation of gene expression.

The result is a global monitoring of TF modulation with great promise as a mechanistically based tool for chemical hazard identification. Cellular Transport Mechanisms of Cytotoxic Metallodrugs: An Overview beyond Cisplatin. The field of medicinal inorganic chemistry has grown consistently during the past 50 years; however, metal-containing coordination compounds represent only a minor proportion of drugs currently on the market, indicating that research in this area has not yet been thoroughly realized.

Although platinum-based drugs as cancer chemotherapeutic agents have been widely studied, exact knowledge of the mechanisms governing their accumulation in cells is still lacking. However, evidence suggests active uptake and efflux mechanisms are involved; this may be involved also in other experimental metal coordination and organometallic compounds with promising antitumor activities in vitro and in vivo, such as ruthenium and gold compounds.

Such knowledge would be necessary to elucidate the balance between activity and toxicity profiles of metal compounds. In this review, we present an overview of the information available on the cellular accumulation of Pt compounds from in vitro, in vivo and clinical studies, as well as a summary of reports on the possible accumulation mechanisms for different families of experimental anticancer metal complexes e.

Finally, we discuss the need for rationalization of the investigational approaches available to study metallodrug cellular transport. Cisplatin and other platinum derivatives are the most widely used chemotherapeutic agents to treat solid tumors including ovarian, head and neck, and testicular germ cell tumors.

A known complication of cisplatin administration is acute kidney injury AKI. The nephrotoxic effect of cisplatin is cumulative and dose-dependent and often necessitates dose reduction or withdrawal. Recurrent episodes of AKI may result in chronic kidney disease. The pathophysiology of cisplatin-induced AKI involves proximal tubular injury, oxidative stress, inflammation, and vascular injury in the kidney.

There is predominantly acute tubular necrosis and also apoptosis in the proximal tubules. There is activation of multiple proinflammatory cytokines and infiltration of inflammatory cells in the kidney. Cisplatin also causes endothelial cell injury.

An understanding of the pathogenesis of cisplatin-induced AKI is important for the development of adjunctive therapies to prevent AKI, to lessen the need for dose decrease or drug withdrawal, and to lessen patient morbidity and mortality. Cisplatin-induced nephrotoxicity and targets of nephroprotection: An update.

Mar Arch Toxicol. Cisplatin is a highly effective antitumor agent whose clinical application is limited by the inherent nephrotoxicity. The current measures of nephroprotection used in patients receiving cisplatin are not satisfactory, and studies have focused on the investigation of new possible protective strategies. Many pathways involved in cisplatin nephrotoxicity have been delineated and proposed as targets for nephroprotection, and many new potentially protective agents have been reported.

The multiple pathways which lead to renal damage and renal cell death have points of convergence and share some common modulators. The most frequent event among all the described pathways is the oxidative stress that acts as both a trigger and a result. The most exploited pathways, the proposed protective strategies, the achievements obtained so far as well as conflicting data are summarized and discussed in this review, providing a general view of the knowledge accumulated with past and recent research on this subject.

Synthesis and Biological Properties. Feb Inorg Chem. Nov Transporters are important mediators of specific cellular uptake and thus, not only for effects, but also for side effects, metabolism, and excretion of many drugs such as cisplatin.

Cisplatin is a potent cytostatic drug, whose use is limited by its severe acute and chronic nephro-, oto-, and peripheral neurotoxicity. For this reason, other platinum derivatives, such as carboplatin and oxaliplatin, with less toxicity but still with antitumoral action have been developed. Several transporters, which are expressed on the cell membranes, have been associated with cisplatin transport across the plasma membrane and across the cell: Some of these transporters are also able to accept other platinum derivatives as substrate.

Since membrane transporters display a specific tissue distribution, they can be important molecules that mediate the entry of platinum derivatives in target and also nontarget cells possibly mediating specific effects and side effects of the chemotherapeutic drug. This paper summarizes the literature on toxicities of cisplatin compared to that of carboplatin and oxaliplatin and the interaction of these platinum derivatives with membrane transporters.

Cisplatin as an Anti-Tumor Drug: Dec Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways.

Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair.

To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates or other drugs and might provide new therapeutic strategies and reduce side effects.

May Mol Pharmacol. Organic cation transporters OCTs are members of the solute carrier 22 SLC22 family of transporter proteins that involved in absorption, distribution, and excretion of organic cations. While OCT3 is localized in the apical AP membrane of enterocytes, the literature is ambiguous about OCT1 mOct1 localization, with some evidence suggesting basolateral BL localization in human and mouse enterocytes.

This is contrary to our preliminary findings showing AP localization of OCT1 in Caco-2 cell monolayers, an established model of human intestinal epithelium. Therefore, this study aims at determining the localization of OCT1 mOct1 in Caco-2 cells, and human and mouse enterocytes. Functional studies using OCT1-specific substrate pentamidine showed transporter-mediated AP but not BL uptake in Caco-2 cells, human and mouse intestinal tissues.

These results are highly significant as they will require re-interpretation of previous drug disposition and drug-drug interaction studies where conclusions were drawn based on BL localization of OCT1 in enterocytes. Most importantly, these results will require revision of the regulatory guidance for industry in the USA and elsewhere since it has stated that OCT1 is basolaterally localized in enterocytes.

The SLC22 family with transporters of organic cations, anions and zwitterions. They participate in small intestinal absorption and hepatic and renal excretion of drugs, xenobiotics and endogenous compounds and perform homeostatic functions in brain and heart. It has been shown that mutations of the SLC22 genes encoding these transporters cause specific diseases like primary systemic carnitine deficiency and idiopathic renal hypouricemia and are correlated with diseases such as Crohn's disease and gout.

Drug-drug interactions at individual transporters may change pharmacokinetics and toxicities of drugs. In the kidney, human organic cation transporters OCTs and multidrug and toxin extrusion proteins MATEs are the major transporters for the secretion of cationic drugs into the urine. However, the expression of these transporters depends on the species of the animal.

Together, these transporters recognize various compounds and have overlapping, but somewhat different, substrate specificities. In this review, we summarize the recent findings and clinical importance of these transporters. Subcellular targets of cisplatin cytotoxicity: An integrated view. Sandra Sancho-Martinez. Cisplatin is a chemotherapeutic drug widely used against a variety of cancers.

Its clinical utility is severely limited by its toxicity, which mainly affects, but is not limited to, the inner ear and renal tubules. Cisplatin toxicity is determined by target tissue and cell accumulation, subcellular handling and trafficking through diverse subcellular structures, and interaction with macromolecules. Cisplatin accumulates and stresses different organelles from which delay signaling is activated, including mitochondria, lysosomes, the endoplasmic reticulum, the nucleus, the cell membrane and cytoskeleton, and can also be found in the cytosol.

This article critically summarizes the available information in order to establish the connection among its known subcellular effects in a hierarchical and integrative framework. Cisplatin causes different types of cell death in a concentration-dependent manner. Knowledge of the events and signaling leading to the different phenotypes is also intertwined within the model, within the scope of the potential utility of this information in the improvement of the pharmacotoxicological profile of this drug.

Perspectives for the key aspects that need to be addressed by future investigation are also outlined. Shifting Sands. May Kidney Int. Nov J Pharmacol Exp Therapeut. We report a systematic comprehensive analysis of the inhibition potency of cimetidine for the influx and efflux transporters of organic cations [human organic cation transporter 1 hOCT1 and hOCT2 and human multidrug and toxin extrusion 1 hMATE1 and hMATE2-K, respectively].

Inhibition constants K i of cimetidine were determined by using five substrates [tetraethylammonium TEA , metformin, 1-methylphenylpyridinium, 4- 4- dimethylamino styryl -N-methylpyridinium, and m-iodobenzylguanidine]. The same tendency was observed for mouse Oct1 mOct1 , mOct2, and mouse Mate1.

Cimetidine was administered to mice by a constant infusion to achieve a plasma unbound concentration of The kidney- and liver-to-plasma ratios of metformin both were increased 2. Cimetidine also increased the kidney-to-plasma ratio of TEA and cephalexin 8. These results suggest that the inhibition of MATEs, but not OCT2, is a likely mechanism underlying the drug-drug interactions with cimetidine in renal elimination.

Apr Br J Pharmacol. The renal organic cation transport system mediates the tubular secretion of cationic compounds including drugs, toxins and endogenous metabolites into urine. Recently, substrate specificity, transcription mechanisms, structure, polymorphisms, in vivo contributions and clinical outcomes on MATE have been investigated intensively.

To view the other articles in this section visit http: Drug transporters of platinum-based anticancer agents and their clinical significance. Platinum-based drugs are among the most active anticancer agents and are successfully used in a wide variety of human malignancies. In this review, we focus on the role of active platinum uptake and efflux systems as determinants of platinum sensitivity and -resistance and their contribution to platinum pharmacokinetics PK and pharmacodynamics PD.

First, the three mostly used platinum-based anticancer agents as well as the most promising novel platinum compounds in development are put into clinical perspective. Next, we describe the presently known potential platinum transporters--with special emphasis on organic cation transporters OCTs --and discuss their role on clinical outcome i.

In addition, transporter-mediated tumour resistance, the impact of potential platinum transporter-mediated drug-drug interactions, and the role of drug transporters in the renal elimination of platinum compounds are discussed. Nov Biol Pharmaceut Bull. The present study examined the influence of cimetidine on the nephrotoxicity and antitumor effects of cisplatin in vitro and in vivo.

Cimetidine and the antioxidant N-acetylcysteine NAC significantly inhibited the in vitro growth inhibition of cisplatin in cells originating from the kidney, but not in SOSN2 osteosarcoma cells. Cimetidine 1 mM also did not influence platinum concentration in the cells, regardless of whether the organic cation transporter 2 OCT2 was expressed.

However, cisplatin did not produce ROS in osteosarcoma cells. From these results, cimetidine clearly inhibits nephrotoxicity induced by cisplatin without any influence on the antitumor activity of cisplatin on osteosarcoma in vitro and in vivo. Mechanisms of Cisplatin Nephrotoxicity. Cisplatin is a widely used and highly effective cancer chemotherapeutic agent.

One of the limiting side effects of cisplatin use is nephrotoxicity. Research over the past 10 years has uncovered many of the cellular mechanisms which underlie cisplatin-induced renal cell death. It has also become apparent that inflammation provoked by injury to renal epithelial cells serves to amplify kidney injury and dysfunction in vivo. This review summarizes recent advances in our understanding of cisplatin nephrotoxicity and discusses how these advances might lead to more effective prevention.

Disruption of multidrug and toxin extrusion MATE1 potentiates cisplatin-induced nephrotoxicity. In the present study, the role of MATE1 in the nephrotoxicity of cisplatin was investigated in vivo and in vitro. Furthermore, the combination of a selective MATE inhibitor, pyrimethamine, with cisplatin also elevated creatinine and BUN levels compared to cisplatin alone.

In conclusion, MATE1 mediates the efflux of cisplatin and is involved in cisplatin-induced nephrotoxicity. Kristin M Bompiani. The development of resistance to cisplatin cDDP is commonly accompanied by reduced drug uptake or increased efflux. Previous studies in yeast and murine embryonic fibroblasts have reported that the copper Cu transporters and chaperones participate in the uptake, efflux, and intracellular distribution of cDDP.

However, there is conflicting data from studies in human cells. All knockout cell lines had slowed growth compared to parental cells, small changes in basal Cu levels, and varying sensitivities to Cu depending on the gene targeted. However, all of the knockouts demonstrated only modest 2 to 5-fold changes in cDDP sensitivity that did not differ from the range of sensitivities of 10 wild type clones grown from the same parental cell population.

We conclude that, under basal conditions, loss of CTR1, CTR2, ATOX1, or CCS does not produce a change in cisplatin sensitivity that exceeds the variance found within the parental population, suggesting that they are not essential to the mechanism by which cDDP enters these cell lines and is transported to the nucleus.

Membrane transporters in drug development. Nat Rev Drug Discov 9: Mar Nat Rev Drug Discov. Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters.

In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions.

The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions for example, exclusion and inclusion criteria , as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling.

Feb Mol Pharmacol. Stephen B. Multiple lines of evidence indicate that the platinum-containing cancer drugs enter cells, are distributed to various subcellular compartments, and are exported from cells via transporters that evolved to manage copper homeostasis.

The cytotoxicity of the platinum drugs is directly related to how much drug enters the cell, and almost all cells that have acquired resistance to the platinum drugs exhibit reduced drug accumulation. The major copper influx transporter, copper transporter 1 CTR1 , has now been shown to control the tumor cell accumulation and cytotoxic effect of cisplatin, carboplatin, and oxaliplatin.

There is a good correlation between change in CTR1 expression and acquired cisplatin resistance among ovarian cancer cell lines, and genetic knockout of CTR1 renders cells resistant to cisplatin in vivo. The expression of CTR1 is regulated at the transcriptional level by copper via Sp1 and at the post-translational level by the proteosome.

General Terms and Conditions. Please note specific policy for live mice. Stock No: Additional Use Restrictions. Also Known As: Pcsk9- Homozygotes have reduced plasma cholesterol levels and accelerated clearance of circulating cholesterol. Donating Investigator Dr. Jay D. Base Price Starting at: Detailed Description Homozygous mice are viable and fertile with no behavioral abnormalities.

Development A targeting vector was designed to replace the region spanning from the C-terminal region of exon 2 through exon 4 of the endogenous gene with a neomycin resistance cassette. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9.

Pcsk9 tm1Jdh Allele Symbol: Northern blot of mutant livers confirmed absence of transcript. Immunoblot of livers further confirmed absence of protein. Mutations Made By Dr. Disease Terms. Research Areas By Genotype This mouse can be used to support research in many areas including: Technical Support. Contact Technical Support. Domestic International. Payment Terms and Conditions Terms are granted by individual review and stated on the customer invoice s and account statement.

Terms Of Use. Terms of Use General Terms and Conditions. Questions about Terms of Use. Use of MICE by companies or for-profit entities requires a license prior to shipping. Licensing Information Phone: Related Strains. A targeting vector containing a neomycin resistance gene was inserted to replace the 3' half of exon 2 through exon 4.

Volume, diameter, type, and a number of lung nodes, pulmonary function, and day lung cancer risk assessment were evaluated. Women who are pregnant or breastfeeding Other chemotherapy treatment less than 4 weeks prior to enrollment Treatment with docetaxel or a platinum agent less than 3 months prior to enrollment Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational. Nat Rev Cancer 7: Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis.

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