A sensitive,rapid and simple liquid chromatography-tandem mass spectrometric（LC-MS/MS） method was developed and validated for the determination of letrozole（LTZ） in nude mouse plasma in the current study,which was...A sensitive,rapid and simple liquid chromatography-tandem mass spectrometric（LC-MS/MS） method was developed and validated for the determination of letrozole（LTZ） in nude mouse plasma in the current study,which was successfully applied to a pharmacokinetic study.Using anastrozole as internal standard（IS）,plasma samples went through a one-step protein precipitation with acetonitrile before determination.The analyte and IS were analyzed on a reversed-phase ZORBAX-SB-C18 column（4.6 mm×250 mm,5 μm） with an isocratic mobile phase consisting of acetonitrile and water containing 0.1% formic acid（v/v） at a flow rate of 1.0 mL/min.The analyte and IS were detected by a triple-quadrupole tandem mass spectrometer,and electrospray and multiple reaction monitoring（MRM） were employed to select LTZ at m/z 286.4/217.1 and IS at m/z 294.1/225.3 simultaneously in the positive ion mode.The calibration curve showed good linearity ranging from 0.8–2000.0 ng/mL（r〉0.99）.The intra-day and inter-day precisions of LTZ were 4.0%–8.4%,with an accuracy of 98.6%–104.9%.Using this method,we successfully characterized the pharmacokinetics（PK） of LTZ by a one-compartment model with first-order absorption in female BALB/c nude mice.展开更多
Sunitinib(SUN)is a multi-targeted receptor tyrosine kinase inhibitor(TKI)that may lead to drug resistance and metastasis because of increased cancer stem-like cells(CSCs)due to the induction of hypoxia.Our group has p...Sunitinib(SUN)is a multi-targeted receptor tyrosine kinase inhibitor(TKI)that may lead to drug resistance and metastasis because of increased cancer stem-like cells(CSCs)due to the induction of hypoxia.Our group has proved that dopamine(DA)can specifically reduce CSC frequency and enhance the response of SUN in drug-resistant breast cancerand non-small cell lung cancer(NSCLC).In this study,DA and SUN combination therapy was investigated in the treatment of pancreatic cancer,a malignant tumor with high mortality rate and very limited therapies.The cytotoxicity assay,clone formation assay and wound healing assay in two pancreatic cancer cell line PANC-1 and SW1990 showed that DA could significantly increase the effect of SUN on cell survival,clone formation ability and migration ability.Besides,SW1990 cell-derived xenograft model and a pancreatic cancer patient-derived xenograft(PDX)model were constructed,further proving that DA could increase the in vivo anti-tumor efficacy of SUN,and could be reversed by SCH23390,a D1 dopamine receptor(D1DR)antagonist.Moreover,the CSC frequency of the combination groups was lower than the control groups or SUN monotherapy groups.In addition,the body weight,H&E staining and blood routine test results showed that the combination therapy was safe.In summary,DA and SUN combination therapy could be a promising strategy for the treatment of pancreatic cancer.展开更多
基金National Natural Science Foundation of China(Grant No.81673500)Innovation Team of Ministry of Education(Grant No.BMU2017TD003)
文摘A sensitive,rapid and simple liquid chromatography-tandem mass spectrometric（LC-MS/MS） method was developed and validated for the determination of letrozole（LTZ） in nude mouse plasma in the current study,which was successfully applied to a pharmacokinetic study.Using anastrozole as internal standard（IS）,plasma samples went through a one-step protein precipitation with acetonitrile before determination.The analyte and IS were analyzed on a reversed-phase ZORBAX-SB-C18 column（4.6 mm×250 mm,5 μm） with an isocratic mobile phase consisting of acetonitrile and water containing 0.1% formic acid（v/v） at a flow rate of 1.0 mL/min.The analyte and IS were detected by a triple-quadrupole tandem mass spectrometer,and electrospray and multiple reaction monitoring（MRM） were employed to select LTZ at m/z 286.4/217.1 and IS at m/z 294.1/225.3 simultaneously in the positive ion mode.The calibration curve showed good linearity ranging from 0.8–2000.0 ng/mL（r〉0.99）.The intra-day and inter-day precisions of LTZ were 4.0%–8.4%,with an accuracy of 98.6%–104.9%.Using this method,we successfully characterized the pharmacokinetics（PK） of LTZ by a one-compartment model with first-order absorption in female BALB/c nude mice.
基金National Natural Science Foundation of China(Grant No.81473277)Innovation Team of Ministry of Education(Grant No.BMU2017TD003)。
文摘Sunitinib(SUN)is a multi-targeted receptor tyrosine kinase inhibitor(TKI)that may lead to drug resistance and metastasis because of increased cancer stem-like cells(CSCs)due to the induction of hypoxia.Our group has proved that dopamine(DA)can specifically reduce CSC frequency and enhance the response of SUN in drug-resistant breast cancerand non-small cell lung cancer(NSCLC).In this study,DA and SUN combination therapy was investigated in the treatment of pancreatic cancer,a malignant tumor with high mortality rate and very limited therapies.The cytotoxicity assay,clone formation assay and wound healing assay in two pancreatic cancer cell line PANC-1 and SW1990 showed that DA could significantly increase the effect of SUN on cell survival,clone formation ability and migration ability.Besides,SW1990 cell-derived xenograft model and a pancreatic cancer patient-derived xenograft(PDX)model were constructed,further proving that DA could increase the in vivo anti-tumor efficacy of SUN,and could be reversed by SCH23390,a D1 dopamine receptor(D1DR)antagonist.Moreover,the CSC frequency of the combination groups was lower than the control groups or SUN monotherapy groups.In addition,the body weight,H&E staining and blood routine test results showed that the combination therapy was safe.In summary,DA and SUN combination therapy could be a promising strategy for the treatment of pancreatic cancer.
