Conjunctive therapy of cisplatin with the OCT2 inhibitor cimetidine: influence on antitumor efficacy and systemic clearance.
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):585-92. doi: 10.1038/clpt.. Epub
2013 Jul 17.Conjunctive therapy of cisplatin with the OCT2 inhibitor cimetidine: influence on antitumor efficacy and systemic clearance.1, , , , , , , , .1Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee.AbstractThe organic cation transporter 2 (OCT2) regulates uptake of cisplatin in proximal tubules, and inhibition of OCT2 protects against severe cisplatin-induced nephrotoxicity. However, it remains uncertain whether potent OCT2 inhibitors, such as cimetidine, can influence the antitumor properties and/or disposition of cisplatin. Using an array of preclinical assays, we found that cimetidine had no effect on the uptake and cytotoxicity of cisplatin in ovarian cancer cells with high OCT2 mRNA levels (IGROV-1 cells). Moreover, the antitumor efficacy of cisplatin in mice bearing luciferase-tagged IGROV-1 xenografts was unaffected by cimetidine (P = 0.39). Data obtained in 18 patients receiving cisplatin (100 mg/m(2)) in a randomized crossover fashion with or without cimetidine (800 mg × 2) revealed that cimetidine did not alter exposure to unbound cisplatin, a marker of antitumor efficacy (4.37 vs. 4.38 ug·h/ P = 0.86). These results support the future clinical exploration of OCT2 inhibitors as specific modifiers of cisplatin-induced nephrotoxicity.PMID:
[PubMed - indexed for MEDLINE] PMCID: PMC3832209 Expression of SLC22A2 (OCT2) normalized to expression of GAPDH, in IGROV-1 and SKOV-3 tumor cells (a). Cellular accumulation of platinum in IGROV-1 cells as well as HEK293 cells transfected with OCT2 or a vector control following a 30 minute incubation with cisplatin (500μM) in the absence or presence of cimetidine (1 mM) (b). Survival of IGROV-1 cells exposed to various concentrations of cisplatin and normalized to untreated controls in the presence or absence of cimetidine (100 μM) (c). Error bars represent standard error of the mean (n=6).Clin Pharmacol Ther. ;94(5):585-592.Change in body weight from baseline of female immunodeficient CD-1 nu/nu mice injected with IGROV-1 cells following 7 and 14 days of receiving cisplatin (10 mg/kg i.p.), cimetidine (7.5 mg/kg i.v.) or a combination of cisplatin and cimetidine (a). Representative luminescence images of female immunodeficient CD-1 nu/nu mice bearing IGROV-1 cells following 14 days of receiving cisplatin (10 mg/kg i.p.) or a combination of cisplatin and cimetidine (7.5 mg/kg i.v.) (b). Signal intensity is measured by quantitative biophotonic imaging analysis (photons/sec/cm2/sr). Tumor growth and volume as measured by luciferase activity in female immunodeficient CD-1 nu/nu mice injected with IGROV-1 cells following 7 and 14 days of receiving cisplatin (10 mg/kg i.p.), cimetidine (7.5 mg/kg i.v.) or a combination of cisplatin and cimetidine (c). Error bars represent standard error of the mean (n=6). P-values above the bars denote statistical comparison between treatments.Clin Pharmacol Ther. ;94(5):585-592.Cellular localization of OCT2 (red) in IGROV-1 (a) and SKOV-3 cells (b), or HEK293 cells transfected with OCT2 (c), or a vector control (d). Cells were also co-stained with phalloidin (green) and DAPI (blue) to visualize actin and DNA, respectively.Clin Pharmacol Ther. ;94(5):585-592.Systemic levels of unbound cimetidine and unbound cisplatin in patients enrolled in Arm A (a) or Arm B (b) over time. Data is represented by mean values and error bars represent standard error of the mean (Arm A, n = 10; Arm B, n = 8).Clin Pharmacol Ther. ;94(5):585-592.The area under the curve (AUC) of unbound cisplatin in patients who received co-treatment with cimetidine in the first cycle only (Arm A) (a) or second cycle only (Arm B) (b). The overall mean clearance of unbound cisplatin in patients who received co-treatment with cimetidine in the first cycle only (Arm A) (c) or second cycle only (Arm B) (d). The difference in pharmacokinetics of cisplatin between the period without and the period with concomitant use of cimetidine, was evaluated using a paired Student’s t–test for comparison of the mean absolute difference between both periods.Clin Pharmacol Ther. ;94(5):585-592.Publication TypesMeSH TermsSubstancesGrant SupportFull Text SourcesOther Literature SourcesMedicalMolecular Biology DatabasesMiscellaneous
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After----for 69 days in a mine about 2,401 feet below the surface of a desert,the 33 chile miners were finally saved on Oct.14.2010.横线处为什么填being trapped 不是 直接填 trapped .
After----for 69 days in a mine about 2,401 feet below the surface of a desert,the 33 chile miners were finally saved on Oct.14.2010.横线处为什么填being trapped 不是 直接填 trapped .
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B B接段时间 B 选B for接时间段~~~ for. 选B for接时间段~~~ 相信大家没有错的！Oxaliplatin-induced neurotoxicity is dependent on the organic cation transporter OCT2.
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2013 Jul 2;110(27):. doi: 10.1073/pnas.. Epub
2013 Jun 17.Oxaliplatin-induced neurotoxicity is dependent on the organic cation transporter OCT2.1, , , , , , , , , .1Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.AbstractOxaliplatin is an integral component of colorectal cancer therapy, but its clinical use is associated with a dose-limiting peripheral neurotoxicity. We found that the organic cation transporter 2 (OCT2) is expressed on dorsal root ganglia cells within the nervous system where oxaliplatin is known to accumulate. Cellular uptake of oxaliplatin was increased by 16- to 35-fold in cells overexpressing mouse Oct2 or human OCT2, and this process was associated with increased DNA platination and oxaliplatin-induced cytotoxicity. Furthermore, genetic or pharmacologic knockout of Oct2 protected mice from hypersensitivity to cold or mechanical-induced allodynia, which are established tests to assess acute oxaliplatin-induced neurotoxicity. These findings provide a rationale for the development of targeted approaches to mitigate this debilitating toxicity. KEYWORDS:
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[PubMed - indexed for MEDLINE] PMCID: PMC3704038 Human and murine OCT2 expression as a mediator of oxaliplatin uptake and cytotoxicity. (A–C) Transport of oxaliplatin by human OCT2 (hOCT2) (A) mouse Oct2 (mOct2) (B) and mouse Oct1 (mOct1) (C) transfected in HEK293 cells (500 uM; 30-min incubations). (D) Platinum (Pt)-DNA adduct formation in HEK293 cells transfected with hOCT2 following exposure to oxaliplatin (500 uM; 30-min incubations). (E) Cell growth inhibition induced by various concentrations of oxaliplatin in HEK293 cells transfected with hOCT2 or VC. The inset shows the estimated concentration associated with 50% growth inhibition (IC50) and the associated 95% confidence intervals (95% CIs). (F) Inhibition of cellular uptake of oxaliplatin (500 uM; 30-min incubations) with cimetidine (1 mM; white bars) in transfected HEK293 cells. (G) Inhibition of 14C-oxaliplatin (2 uM) uptake with various concentrations of cimetidine in HEK293 cells transfected with hOCT2 or mOct2 (30-min incubations). The inset shows the estimated concentration associated with 50% inhibition of uptake (IC50) and the associated 95% CIs. (H) Concentration-dependence of oxaliplatin transport by mOct2 and hOCT2 transfected into HEK293 cells. (I) Concentration-dependence of cisplatin transport by hOCT2 transfected into HEK293 cells (16). Data represent the net difference in uptake observed in cells with or without the transporter. Km denotes the Michaelis–Menten constant, and Vmax denotes the maximum velocity. Data represent the mean of triplicate observations from experiments performed on at least three separate occasions, and are expressed as average percentage of uptake values in cells transfected with an empty vector (VC). Error bars represent SE. The asterisk denotes significant differences from VC (P & 0.05).Proc Natl Acad Sci U S A. 2013 July 2;110(27):.Identification of OCT2 as a transporter in dorsal root ganglia (DRG). (A) Detection of Oct2 by immunofluorescence in DRG of wild-type and Oct1/2(-/-) mice. Oct2 is depicted by green fluorescence, whereas DNA is depicted in blue (DAPI). (B) OCT2 expression detected in human DRG (Human 1 and Human 2) by RT-PCR (depicted by the 128-bp product). Oct2 expression was also detected in DRG of wild-type mice (lane 3; 306bp product) but not in DRG isolated from Oct1/2(-/-) mice.Proc Natl Acad Sci U S A. 2013 July 2;110(27):.Oxaliplatin disposition and toxicity in Oct1/2(-/-) mice. (A and B) Time course of urinary excretion (A) and total plasma concentrations (Ct) and unbound plasma concentrations (Cu) (B) in male wild-type (urinary excretion: n = 29; plasma concentrations: n = 4) and Oct1/2(-/-) mice (urinary excretion: n = 25; plasma concentrations: n = 4) following a single i.p. administration of oxaliplatin (40 mg/kg). Data are presented as the mean (symbols or bars) and SE (error bars). The asterisk denotes a significant difference from wild-type mice (P & 0.05). (C and D) Cumulative overall survival (C) and overall toxicity (D) as determined from weight changes from baseline in male wild-type and Oct1/2(-/-) mice following a single i.p. administration of oxaliplatin (40 mg/kg). Data are presented as the mean (symbols) and SE (error bars) of six observations per group. (E) Representative histopathology in wild-type and Oct1/2(-/-) mice before (“untreated”) and 72-h after administration of oxaliplatin (40 mg/kg) (“treated”). Both in wild-type and Oct1/2(-/-) mice, the main lesions were damage to the small-intestinal epithelium (40× magnification) and bone marrow hypocellularity (10× magnification). The former was associated with crypt loss, implying the prior occurrence of crypt necrosis, the latter with severe myelosuppression.Proc Natl Acad Sci U S A. 2013 July 2;110(27):.Sensitivity to cold in response to oxaliplatin. (A) Baseline values for the number of paw lifts or licks performed by wild-type or Oct1/2(-/-) mice exposed to -4 °C for 5 min. (B) The number of paw lifts or licks performed by wild-type FVB mice exposed to various temperatures (-4 °C, 4 °C, and 30 °C) for 5 min both before and after treatment with oxaliplatin (40 mg/kg). Data are presented as the mean (symbols or bars) and SE (error bars) where n represents the number of events observed. P values above the bars denote statistical comparison between baseline and after treatment.Proc Natl Acad Sci U S A. 2013 July 2;110(27):.OCT2 regulation of oxaliplatin-induced neuropathy. (A) Sensitivity to cold associated with a single dose of oxaliplatin (40 mg/kg) in wild-type and Oct1/2(-/-) mice, as determined by a cold-plate test. Data are presented as the number of paw lifts or licks at baseline and following exposure to a temperature of -4 °C for 5 min at 24 h [wild type: n = 25; Oct1/2(-/-): n = 17] or 48 h [wild type: n = 25; Oct1/2(-/-): n = 16] after drug administration. (B) Mechanical allodynia associated with a single dose of oxaliplatin (40 mg/kg) in wild-type and Oct1/2(-/-) mice, as determined by a Von Frey Hairs test. Data are presented as the force required to promote paw withdrawal in grams (g) at baseline and following 24 h [wild type: n = 11; Oct1/2(-/-): n = 11] or 48 h [wild type: n = 11, Oct1/2(-/-): n = 10] after drug administration. (C) Change in sensitivity to cold in wild-type (n = 7) and Oct1/2(-/-) (n = 7) mice 24 h after receiving oxaliplatin (5 mg/kg) alone or in combination with cimetidine (30 mg/kg, i.v. bolus). (D) Change in mechanical allodynia in wild-type (n = 8) and Oct1/2(-/-) (n = 7) mice 48 h after receiving oxaliplatin (5 mg/kg) alone or in combination with cimetidine (30 mg/kg, i.v. bolus). (E) Change in sensitivity to cold in wild-type mice (n = 7) 24 h after receiving oxaliplatin (5 mg/kg) alone (n = 7) or in combination with cimetidine (i.v. bolus) at a concentration of 5 mg/kg (n = 7) or 30 mg/kg (n = 9). Bars represent the mean and error bars are the SE. The asterisk denotes significant difference from baseline and between strains (P & 0.05).Proc Natl Acad Sci U S A. 2013 July 2;110(27):.Transporter genes in dorsal root ganglia of Oct1/2(-/-) mice. Comparative expression of 84 transporter genes at baseline in dorsal root ganglia of wild-type mice and Oct1/2(-/-) mice (n = 3 each). Each symbol represents an average reading for a single gene, the solid line is the line of identity, and the dotted lines are the 95% CIs. The colored symbols represent transporter genes previously implicated in oxaliplatin toxicity.Proc Natl Acad Sci U S A. 2013 July 2;110(27):.Publication TypesMeSH TermsSubstancesGrant SupportFull Text SourcesOther Literature SourcesMolecular Biology DatabasesMiscellaneous
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