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Cisplatin is a cytotoxic platinum compound, used in the treatment of several solid tumors. Cisplatin and to a greater extent its hydrolysis product monohydrated cisplatin are responsible for side-effects like nephrotoxicity. A sen...
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Cisplatin is a cytotoxic platinum compound, used in the treatment of several solid tumors. Cisplatin and to a greater extent its hydrolysis product monohydrated cisplatin are responsible for side-effects like nephrotoxicity. A sensitive, accurate and precise method was developed to simultaneously determine cisplatin and monohydrated cisplatin in plasma. The compounds were separated by high-performance liquid chromatography and quantified by off-line furnace atomic absorption spectrophotometry. The linear ranges for cisplatin and monohydrated cisplatin in deproteinized plasma were 60-600 and 87.5i-700 nM, respectively. From plasma, the mean recovery of cisplatin was 83.2% and that of monohydrated cisplatin 79.1%. The lower limits of quantification of cisplatin and monohydrated cisplatin in deproteinized plasma were 60 and 87.5 nM, respectively. Over the whole calibration range, the within- and between-day accuracy of intact cisplatin ranged from 100.7 to 111.4 and 94.8-102.0%, respectively. The within- and between-day accuracy of monohydrated cisplatin ranged from 107.1 to 113.3 and 101.4-104.9%, respectively. The within-day and between-day precision of cisplatin ranged from 3.4 to 11.5 and 7.3-10.3%, respectively. For monohydrated cisplatin, the within-day and between-day precision ranged from 3.7 to 6.2 and 5.6-7.9%, respectively. Currently, the developed assay has been implemented in pharmacokinetic studies of patients treated with cisplatin alone or in combination with other drugs.
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Background:Managed Ventricular Pacing (MVP) and Search AV+ (SAV+) are two pacing algorithms designed to reduce ventricular pacing. MVP promotes conduction by operating in AAI/R mode with backup ventricular pacing during atrioventr...
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Background:Managed Ventricular Pacing (MVP) and Search AV+ (SAV+) are two pacing algorithms designed to reduce ventricular pacing. MVP promotes conduction by operating in AAI/R mode with backup ventricular pacing during atrioventricular block (AVB). SAV+ operates in DDD/R mode with a nominal AV extension of 290 ms during atrial sensing and 320 ms during atrial pacing. The reduction in ventricular pacing was compared with these two algorithms in pacemaker patients. Methods:The EnRhythm and EnPulse clinical studies assessed the percentage of ventricular pacing (%VP) after 1 month. Each patient's AVB status was assigned using the following hierarchical categories: persistent third-degree AVB (p3AVB), episodic third-degree AVB (e3AVB), second-degree AVB (2AVB), first-degree AVB (1AVB), and no AVB (nAVB). The%VP was tabulated for each AVB status category. Results:Data were available from 322 patients of whom 129 received DDD(R) pacing with the MVP algorithm activated and 193 patients with DDD(R) pacing and the SAV+ function activated, each for a month period. MVP resulted in a significantly lower median%VP than SAV+ in all AVB categories except for p3AVB: nAVB (0.3 vs 2.9, P < 0.0001), 1AVB (0.9% vs 80.6%, P < 0.0001), 2AVB (37.6 vs 99.3, P< 0.002), e3AVB (1.2 vs 42.2, P = 0.02), p3AVB (98.9 vs 100, P = 1.00). Conclusion:MVP resulted in a greater reduction in%VP than SAV+ across all patient groups except persistent third-degree AV block. The greatest reduction in%VP was observed in patients with mildly impaired AV conduction.
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Defects in intracellular accumulation of the antitumour drug cisplatin are a commonly observed feature in the cells selected for cisplatin resistance. Copper transporter 1 (CTR1) has been suggested to play an important role in dru...
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Defects in intracellular accumulation of the antitumour drug cisplatin are a commonly observed feature in the cells selected for cisplatin resistance. Copper transporter 1 (CTR1) has been suggested to play an important role in drug uptake and resistance. Here, we describe a detailed investigation of the involvement of CTR1 in cisplatin uptake and its relevance for cisplatin resistance using a well characterised sensitive/cisplatin-resistant cell line pair: A2780 human ovarian carcinoma cell line and its cisplatin-resistant variant A2780cis. A2780cis cells showed decreased cisplatin accumulation and lower CTR1 expression compared to A2780 cells. Co-incubation with copper sulphate affected neither cisplatin accumulation (determined by flameless atomic absorption spectrometry) nor its cytotoxicity (determined using an MTT-assay, MTT = 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide). In both cell lines, CTR1 was localised near the nucleus as found using confocal fluorescence microscopy. The steady-state localisation of the protein in perinuclear region appears to involve its continuous endocytosis from cell surface. In contrast to copper, cisplatin exposure had no influence on the sub cellular localisation of CTR1. Co-localisation between CTR1 and a fluorescent cisplatin analogue labelled with carboxyfluorescein-diacetate could be observed in vesicular structures when continuous retrieval of the protein from cell membrane was inhibited. Our results strongly suggest that CTR1 mediates cisplatin uptake in the cell lines studied. Upon its transport across the plasma membrane by CTR1 the platinum drug is likely to be internalised along with the protein. Our findings imply that reduced CTR1 expression accounts for decreased cisplatin accumulation and represents one of the determinants of cisplatin resistance in A2780cis cell line.
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Acute kidney injury (AKI) is a growing global health problem with increased mortality and morbidity. Cisplatin is achemotherapy drug first introduced in 1978, and since then, it became one of the most widely used and successful an...
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Acute kidney injury (AKI) is a growing global health problem with increased mortality and morbidity. Cisplatin is achemotherapy drug first introduced in 1978, and since then, it became one of the most widely used and successful anti-cancer medication. However, there are risks associated with cisplatin administration, such as nephrotoxicity. Mechanisms of nephrotoxicity include proximal tubular injury, DNA damage, apoptosis, inflammation, oxidative stress, and vascular injury. Although various protocols are being used in clinical practice in nephrotoxicity prevention due to cisplatin, there are no clear guidelines regarding this approach. Most recommendations include hydration and avoiding additional nephrotoxic drugs. To prevent nephrotoxicity, future perspectives could rely on natural products, such as flavonoids or saponins or pharmacological products, such as aprepitant, but data are scarce in this direction. Repetitive administration of cisplatin could cause subclinical kidney injury, which over time, leads to chronic kidney disease (CKD). Therefore, more studies are needed to determine possible ways to prevent nephrotoxicity and avoid the burden of CKD worldwide.
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Abstract Concurrent chemoradiotherapy with 3‐weekly cisplatin 100?mg/m2 has been the standard of care for locoregionally advanced head and neck cancer (LA‐HNC) with level I evidence. While the outcomes in terms of efficacy have ...
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Abstract Concurrent chemoradiotherapy with 3‐weekly cisplatin 100?mg/m2 has been the standard of care for locoregionally advanced head and neck cancer (LA‐HNC) with level I evidence. While the outcomes in terms of efficacy have been well established, the toxicity profile, compliance, and real‐world applicability has been an area of ongoing concern for this regimen, leading the oncologists to explore weekly cisplatin chemoradiotherapy regimen to potentially address the issue. A review of literature was conducted in Pubmed, Scopus, and Medline to compare and evaluate the present role of weekly cisplatin chemotherapy along with radiotherapy versus 3‐weekly cisplatin chemotherapy along with radiotherapy in both adjuvant and definitive settings for locoregionally advanced head and neck cancers. Nasopharyngeal subsites were excluded from the literature review and 50 relevant articles were included in the analysis. Recently published evidences of noninferiority of weekly over 3‐weekly cisplatin chemoradiotherapy regimen in definitive as well as adjuvant settings in locoregionally advanced head and neck cancers is highlighted and interpreted. Results supporting and against the above in different publications is elaborated in this article. Trials designed to demonstrate noninferiority of the weekly cisplatin chemoradiotherapy regimen over 3‐weekly regimen, especially in definitive setting may conclude the debate in future. A lacunae in the existing literature is noted in the form of lack of superiority trials on the above topic, which may impact future conclusions.
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A novel method for the study of the interaction of the platinum drug cisdiamminedichloroplatinum(II) (cis-DDP or cisplatin) with 50-mer oligonucleoticles that were printed in high throughput microarray format is introduced. our ai...
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A novel method for the study of the interaction of the platinum drug cisdiamminedichloroplatinum(II) (cis-DDP or cisplatin) with 50-mer oligonucleoticles that were printed in high throughput microarray format is introduced. our aim has been to identify sequence level differences in the interaction of various drug candidates that may serve to enable rational targeting of drugs to specific genes. A microarray of 26 control genes commonly used in oligonucleoticle, Affymetrix and c-DNA microarray platforms were microcontact spotted as amine-terminated 50-mer oligonucleoticles onto glycidoxypropyltimethoxy silane (GPMS)-modified glass slides. The generalized study format involved hybridization of probes with to fluorescently labeled complements as target followed by confocal imaging to reveal original spot intensities. Microarrays were then incubated at 37 degrees C with hydrolysed cisplatin while in hybridization cassettes, washed in buffer and then scanned again to reveal secondary intensities. We have investigated the influence of cisplatin to stabilize the relative fluorescence intensity via intrastrand crosslinking by studying the impact of varying drug:probe-DNA mole ratio (on (blank), 1:1, 25:1 and 50:1) and annealing temperatures (36, 46, or 56 degrees C) on retained intensity. ANOVA revealed that 4 of the to genes demonstrated (p < 0.0001) the expected result of increased signal retention with decreased temperature and increased drug concentration.
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Chemoresistance is the primary obstacle in the treatment of locally advanced and metastatic nasopharyngeal carcinoma (NPC). Recent evidence suggests that the transcription factor forkhead box M1 (FoxM1) is involved in chemoresista...
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Chemoresistance is the primary obstacle in the treatment of locally advanced and metastatic nasopharyngeal carcinoma (NPC). Recent evidence suggests that the transcription factor forkhead box M1 (FoxM1) is involved in chemoresistance. Our group previously confirmed that FoxM1 is overexpressed in NPC. In this study, we investigated the role of FoxM1 in cisplatin resistance of the cell lines 5–8F and HONE-1 and explored its possible mechanism. Our results showed that FoxM1 and NBS1 were both overexpressed in NPC tissues based on data from the GSE cohort (GSE12452). Then, we measured FoxM1 levels in NPC cells and found FoxM1 was overexpressed in NPC cell lines and could be stimulated by cisplatin. MTT and clonogenic assays, flow cytometry, γH2AX immunofluorescence, qRT-PCR, and western blotting revealed that downregulation of FoxM1 sensitized NPC cells to cisplatin and reduced the repair of cisplatin-induced DNA double-strand breaks via inhibition of the MRN (MRE11-RAD50-NBS1)-ATM axis, which might be related to the ability of FoxM1 to regulate NBS1. Subsequently, we demonstrated that enhanced sensitivity of FoxM1 knockdown cells could be reduced by overexpression of NBS1. Taken together, our data demonstrate that downregulation of FoxM1 could improve the sensitivity of NPC cells to cisplatin through inhibition of MRN-ATM-mediated DNA repair, which could be related to FoxM1-dependent regulation of NBS1.
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Loco-regional delivery of cisplatin by Intraperitoneal (IP) administration in ovarian cancer is highly advantageous, since it exposes high concentrations of cisplatin to tumors in the peritoneal cavity. PAMAM-dendrimer-cisplatin c...
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Loco-regional delivery of cisplatin by Intraperitoneal (IP) administration in ovarian cancer is highly advantageous, since it exposes high concentrations of cisplatin to tumors in the peritoneal cavity. PAMAM-dendrimer-cisplatin complexes are expected to enhance the penetration of tumors in the peritoneal cavity, and aid in enhancing antitumor efficacy of cisplatin. In the present study, PAMAM G4 NH2 and Biotin PAMAM G4 NH2 dendrimer cisplatin complexes were administered intraperitoneally to SKOV xenografted athymic nude mice at a dose of 4 mg/kg. The increase in lifespan of tumor bearing mice and biodistribution of cisplatin in various organs was evaluated after IP administration of cisplatin and dendrimer-cisplatin complexes. The lifespan of mice increased by 41.93% and 25.8%, after treatment with PAMAM G4 NH2 and Biotin PAMAM G4 NH2 dendrimer cisplatin complexes, respectively. A 3-fold increase in the levels of platinum in plasma was observed, after administration of both PAMAM G4 NH2 and Biotin PAMAM G4 NH2 dendrimer cisplatin complexes. Biodistribution studies have shown higher accumulation of platinum in liver, spleen and kidneys with PAMAM G4 NH2 dendrimer-cisplatin complexes. The increased plasma concentration and enhanced tissue accumulation after IP administration of dendrimer-cisplatin complexes offer advantage of administering low dose of cisplatin, which would reduce the dose-dependent toxic effects of cisplatin.
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Our aim was to explore the involvement of the transcriptional suppressor GCF2 in silencing RhoA, disorganization of the cytoskeleton, mislocalization of MRP1, and sensitivity to anticancer agents as an upstream gene target in canc...
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Our aim was to explore the involvement of the transcriptional suppressor GCF2 in silencing RhoA, disorganization of the cytoskeleton, mislocalization of MRP1, and sensitivity to anticancer agents as an upstream gene target in cancer therapy. Increased expression of GCF2 was found in human cisplatin-resistant cells, and overexpression in GCF2-transfected cells results in loss of RhoA expression and disruption of the actin/filamin network. In consequence, the membrane transporter MRP1 was internalized from the cell surface into the cytoplasm, rendering cells sensitive to doxorubicin by more than 10-fold due to increased accumulation of doxorubicin in the cells. The GCF2 transfectants also showed reduced accumulation of cisplatin and increased resistance. siRNA targeted to GCF2 suppressed the expression of GCF2 in cisplatin-resistant cells, reactivated RhoA expression, and restored the fine structure of actin microfilaments. MRP1 was also relocated to the cell surface. siRNA targeted to RhoA increased resistance 3-fold in KB-3-1 and KB-CP.5 cells. These data for the first time demonstrate a novel complex regulatory pathway downstream from GCF2 involving the small GTPase RhoA, actin/filamin dynamics, and membrane protein trafficking. This pathway mediates diverse responses to cytotoxic compounds, and also provides a molecular basis for further investigation into the pleiotropic resistance mechanism at play in cisplatin-resistant cells.
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