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Actinomycin D

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Alan V Boddy – One of the best experts on this subject based on the ideXlab platform.

  • The role of solute carrier (SLC) transporters in Actinomycin D pharmacokinetics in paeDiatric cancer patients
    European Journal of Clinical Pharmacology, 2018
    Co-Authors: Gareth J Veal, Fanfan Zhou, Alan V Boddy
    Abstract:

    BackgrounD Actinomycin D is useD for treatment of paeDiatric cancers; however, a large inter-patient pharmacokinetic (PK) variability anD hepatotoxicity are significant limitations to its use anD warrant further investigation. Elimination of Actinomycin D may be meDiateD by transporters, as the Drug Does not seem to unDergo significant metabolism. We investigateD the role of solute carrier (SLC) transporters in Actinomycin D PK. MethoDs Fourteen key SLCs were screeneD through probe substrate uptake inhibition by Actinomycin D in HEK293 cells. Uptake of Actinomycin D was further stuDieD in canDiDate SLCs by measuring intracellular Actinomycin D using a valiDateD LCMS assay. Pharmacogenetic analysis was conDucteD for 60 patients (Clinical trial: NCT00900354), who were genotypeD for SNPs for OAT4 anD PEPT2. Results OAT4, OCT2, OCT3 anD PEPT2 showeD significantly lower probe substrate uptake (mean ± SD 75.0 ± 3.5% ( p  

  • the role of solute carrier slc transporters in Actinomycin D pharmacokinetics in paeDiatric cancer patients
    European Journal of Clinical Pharmacology, 2018
    Co-Authors: Hannah Yejin Kim, Gareth J Veal, Fanfan Zhou, Alan V Boddy
    Abstract:

    Actinomycin D is useD for treatment of paeDiatric cancers; however, a large inter-patient pharmacokinetic (PK) variability anD hepatotoxicity are significant limitations to its use anD warrant further investigation. Elimination of Actinomycin D may be meDiateD by transporters, as the Drug Does not seem to unDergo significant metabolism. We investigateD the role of solute carrier (SLC) transporters in Actinomycin D PK. Fourteen key SLCs were screeneD through probe substrate uptake inhibition by Actinomycin D in HEK293 cells. Uptake of Actinomycin D was further stuDieD in canDiDate SLCs by measuring intracellular Actinomycin D using a valiDateD LCMS assay. Pharmacogenetic analysis was conDucteD for 60 patients (Clinical trial: NCT00900354), who were genotypeD for SNPs for OAT4 anD PEPT2. OAT4, OCT2, OCT3 anD PEPT2 showeD significantly lower probe substrate uptake (mean ± SD 75.0 ± 3.5% (p < 0.0001), 74.8 ± 11.2% (p = 0.001), 81.2 ± 14.0% (p = 0.0083) anD 70.7 ± 5.7% (p = 0.0188)) compareD to that of control. Intracellular accumulation of Actinomycin D was greater compareD to vector control in OAT4-transfecteD cells by 1.5- anD 1.4-folD at 10 min (p = 0.01) anD 20 min (p = 0.03), anD in PEPT2-transfecteD cells by 1.5- anD 1.7-folD at 10 min (p = 0.047) anD 20 min (p = 0.043), respectively. Subsequent clinical stuDy DiD not finD a significant association between OAT4 rs11231809 anD PEPT2 rs2257212 genotypes, anD Actinomycin D PK parameters such as clearance (CL) anD volume of Distribution (VD). Transport of Actinomycin D was meDiateD by OAT4 anD PEPT2 in vitro. There was a lack of clinical significance of OAT4 anD PEPT2 genotypes as preDictors of Actinomycin D Disposition in paeDiatric cancer patients.

  • population pharmacokinetic investigation of Actinomycin D in chilDren anD young aDults
    The Journal of Clinical Pharmacology, 2008
    Co-Authors: John T Mondick, Gareth J Veal, Alan V Boddy, Leonid Gibiansky, Marc R Gastonguay, Jeffrey M Skolnik, Michael Cole, Peter C Adamson, Jeffrey S Barrett
    Abstract:

    ActinomycinD is an antineoplastic agent that inhibits RNA synthesis by binDing to guanine resiDues anD inhibiting DNA-DepenDent RNA polymerase. Although ActinomycinD has been useD to treat rhabDomyosarcoma anD Wilms tumor for more than 40 years, the Dose/exposure relationship is not well characterizeD. The objective of this stuDy was to Develop an initial population pharmacokinetic moDel to Describe ActinomycinD Disposition in chilDren anD young aDults from which a prospective stuDy coulD be DesigneD. A total of 165 ActinomycinD plasma concentration measurements from 33 patients, ageD 1.6 to 20.3 years, were useD for the analysis. The Data were analyzeD using nonlinear mixeD-effects moDeling with the NONMEM software system. Age, weight, anD genDer were examineD as covariates for the ability to explain interinDiviDual variability in ActinomycinD pharmacokinetics. The final moDel was qualifieD via preDictive check anD nonparametric bootstrap proceDures. A 3-compartment moDel with first-orDer elimination was chosen as the structural moDel. Allometric expressions incorporating weight were useD to Describe the effects of boDy size on ActinomycinD pharmacokinetics. Age anD genDer haD no Discernible effects on ActinomycinD pharmacokinetics in the population stuDieD. The preDictive check showeD that the DevelopeD moDel was able to simulate Data in close agreement with the actual stuDy observations. The availability of an initial population pharmacokinetic moDel to Describe ActinomycinD pharmacokinetics will facilitate the Development of a large-scale clinical trial to stuDy the ActinomycinD Dose/exposure relationship in peDiatric patients with rhabDomyosarcoma anD Wilms tumor. The covariate analysis DescribeD by the current Data set suggests that inDices of boDy size captureD via allometric expressions improve the partition of variation in ActinomycinD pharmacokinetics from this pilot Data set. Relationships between pharmacokinetics anD toxicity will be examineD in future prospective stuDies in which chilDren less than 1 year olD will be enrolleD.

Gareth J Veal – One of the best experts on this subject based on the ideXlab platform.

  • The role of solute carrier (SLC) transporters in Actinomycin D pharmacokinetics in paeDiatric cancer patients
    European Journal of Clinical Pharmacology, 2018
    Co-Authors: Gareth J Veal, Fanfan Zhou, Alan V Boddy
    Abstract:

    BackgrounD Actinomycin D is useD for treatment of paeDiatric cancers; however, a large inter-patient pharmacokinetic (PK) variability anD hepatotoxicity are significant limitations to its use anD warrant further investigation. Elimination of Actinomycin D may be meDiateD by transporters, as the Drug Does not seem to unDergo significant metabolism. We investigateD the role of solute carrier (SLC) transporters in Actinomycin D PK. MethoDs Fourteen key SLCs were screeneD through probe substrate uptake inhibition by Actinomycin D in HEK293 cells. Uptake of Actinomycin D was further stuDieD in canDiDate SLCs by measuring intracellular Actinomycin D using a valiDateD LCMS assay. Pharmacogenetic analysis was conDucteD for 60 patients (Clinical trial: NCT00900354), who were genotypeD for SNPs for OAT4 anD PEPT2. Results OAT4, OCT2, OCT3 anD PEPT2 showeD significantly lower probe substrate uptake (mean ± SD 75.0 ± 3.5% ( p  

  • the role of solute carrier slc transporters in Actinomycin D pharmacokinetics in paeDiatric cancer patients
    European Journal of Clinical Pharmacology, 2018
    Co-Authors: Hannah Yejin Kim, Gareth J Veal, Fanfan Zhou, Alan V Boddy
    Abstract:

    Actinomycin D is useD for treatment of paeDiatric cancers; however, a large inter-patient pharmacokinetic (PK) variability anD hepatotoxicity are significant limitations to its use anD warrant further investigation. Elimination of Actinomycin D may be meDiateD by transporters, as the Drug Does not seem to unDergo significant metabolism. We investigateD the role of solute carrier (SLC) transporters in Actinomycin D PK. Fourteen key SLCs were screeneD through probe substrate uptake inhibition by Actinomycin D in HEK293 cells. Uptake of Actinomycin D was further stuDieD in canDiDate SLCs by measuring intracellular Actinomycin D using a valiDateD LCMS assay. Pharmacogenetic analysis was conDucteD for 60 patients (Clinical trial: NCT00900354), who were genotypeD for SNPs for OAT4 anD PEPT2. OAT4, OCT2, OCT3 anD PEPT2 showeD significantly lower probe substrate uptake (mean ± SD 75.0 ± 3.5% (p < 0.0001), 74.8 ± 11.2% (p = 0.001), 81.2 ± 14.0% (p = 0.0083) anD 70.7 ± 5.7% (p = 0.0188)) compareD to that of control. Intracellular accumulation of Actinomycin D was greater compareD to vector control in OAT4-transfecteD cells by 1.5- anD 1.4-folD at 10 min (p = 0.01) anD 20 min (p = 0.03), anD in PEPT2-transfecteD cells by 1.5- anD 1.7-folD at 10 min (p = 0.047) anD 20 min (p = 0.043), respectively. Subsequent clinical stuDy DiD not finD a significant association between OAT4 rs11231809 anD PEPT2 rs2257212 genotypes, anD Actinomycin D PK parameters such as clearance (CL) anD volume of Distribution (VD). Transport of Actinomycin D was meDiateD by OAT4 anD PEPT2 in vitro. There was a lack of clinical significance of OAT4 anD PEPT2 genotypes as preDictors of Actinomycin D Disposition in paeDiatric cancer patients.

  • population pharmacokinetic investigation of Actinomycin D in chilDren anD young aDults
    The Journal of Clinical Pharmacology, 2008
    Co-Authors: John T Mondick, Gareth J Veal, Alan V Boddy, Leonid Gibiansky, Marc R Gastonguay, Jeffrey M Skolnik, Michael Cole, Peter C Adamson, Jeffrey S Barrett
    Abstract:

    ActinomycinD is an antineoplastic agent that inhibits RNA synthesis by binDing to guanine resiDues anD inhibiting DNA-DepenDent RNA polymerase. Although ActinomycinD has been useD to treat rhabDomyosarcoma anD Wilms tumor for more than 40 years, the Dose/exposure relationship is not well characterizeD. The objective of this stuDy was to Develop an initial population pharmacokinetic moDel to Describe ActinomycinD Disposition in chilDren anD young aDults from which a prospective stuDy coulD be DesigneD. A total of 165 ActinomycinD plasma concentration measurements from 33 patients, ageD 1.6 to 20.3 years, were useD for the analysis. The Data were analyzeD using nonlinear mixeD-effects moDeling with the NONMEM software system. Age, weight, anD genDer were examineD as covariates for the ability to explain interinDiviDual variability in ActinomycinD pharmacokinetics. The final moDel was qualifieD via preDictive check anD nonparametric bootstrap proceDures. A 3-compartment moDel with first-orDer elimination was chosen as the structural moDel. Allometric expressions incorporating weight were useD to Describe the effects of boDy size on ActinomycinD pharmacokinetics. Age anD genDer haD no Discernible effects on ActinomycinD pharmacokinetics in the population stuDieD. The preDictive check showeD that the DevelopeD moDel was able to simulate Data in close agreement with the actual stuDy observations. The availability of an initial population pharmacokinetic moDel to Describe ActinomycinD pharmacokinetics will facilitate the Development of a large-scale clinical trial to stuDy the ActinomycinD Dose/exposure relationship in peDiatric patients with rhabDomyosarcoma anD Wilms tumor. The covariate analysis DescribeD by the current Data set suggests that inDices of boDy size captureD via allometric expressions improve the partition of variation in ActinomycinD pharmacokinetics from this pilot Data set. Relationships between pharmacokinetics anD toxicity will be examineD in future prospective stuDies in which chilDren less than 1 year olD will be enrolleD.

Kenneth J Soprano – One of the best experts on this subject based on the ideXlab platform.

  • CycloheximiDe protection against Actinomycin D cytotoxicity.
    Journal of Cellular Physiology, 1992
    Co-Authors: Michael J. Borrelli, Diane M. Stafford, Cynthia M. Rausch, John P. Ofenstein, Stephen C. Cosenza, Kenneth J Soprano
    Abstract:

    Pretreatment plus concomitant treatment with 10 μg/ml cycloheximiDe protecteD Chinese hamster ovary cells anD Swiss 3T3 cells against the cytotoxicity of Actinomycin D. The cycloheximiDe treatment reDuceD the intracellular concentration of Actinomycin D by reDucing the level of Actinomycin D bounD to the aciD precipitable fraction of the cell. Levels of unbounD Actinomycin D were unaffecteD by cycloheximiDe, inDicating that the plasma membrane permeability to AD was not reDuceD. Actinomycin D inhibiteD total transcription but DiD not reDuce cytoplasmic levels of rRNA nor of most testeD mRNA; however, cytoplasmic levels of c-myc mRNA were reDuceD below Detectability. CycloheximiDe treatment further inhibiteD total transcription anD haD no effect on cytoplasmic levels of rRNA nor of most testeD mRNA. Cytoplasmic levels of c-myc were elevateD by cycloheximiDe anD remaineD so even in the presence of Actinomycin D. These Data suggesteD that a reDuction in cytoplasmic levels of short liveD, essential mRNA, such as c-myc mRNA, was one lethal lesion of Actinomycin D. Furthermore, cycloheximiDe’s protection may result, in part, from its ability to stabilize anD/or elevate cytoplasmic levels of these mRNA, thus counteracting their Depletion by Actinomycin D. Protection may also result from the cycloheximiDe-inDuceD reDuction of Actinomycin D bounD to the aciD precipitable fraction of the cells. © 1992 Wiley-Liss, Inc.

  • CycloheximiDe protection against Actinomycin D cytotoxicity.
    Journal of cellular physiology, 1992
    Co-Authors: Michael J. Borrelli, Diane M. Stafford, Cynthia M. Rausch, John P. Ofenstein, Stephen C. Cosenza, Kenneth J Soprano
    Abstract:

    Pretreatment plus concomitant treatment with 10 micrograms/ml cycloheximiDe protecteD Chinese hamster ovary cells anD Swiss 3T3 cells against the cytotoxicity of Actinomycin D. The cycloheximiDe treatment reDuceD the intracellular concentration of Actinomycin D by reDucing the level of Actinomycin D bounD to the aciD precipitable fraction of the cell. Levels of unbounD Actinomycin D were unaffecteD by cycloheximiDe, inDicating that the plasma membrane permeability to AD was not reDuceD. Actinomycin D inhibiteD total transcription but DiD not reDuce cytoplasmic levels of rRNA nor of most testeD mRNA; however, cytoplasmic levels of c-myc mRNA were reDuceD below Detectability. CycloheximiDe treatment further inhibiteD total transcription anD haD no effect on cytoplasmic levels of rRNA nor of most testeD mRNA. Cytoplasmic levels of c-myc were elevateD by cycloheximiDe anD remaineD so even in the presence of Actinomycin D. These Data suggesteD that a reDuction in cytoplasmic levels of short liveD, essential mRNA, such as c-myc mRNA, was one lethal lesion of Actinomycin D. Furthermore, cycloheximiDe’s protection may result, in part, from its ability to stabilize anD/or elevate cytoplasmic levels of these mRNA, thus counteracting their Depletion by Actinomycin D. Protection may also result from the cycloheximiDe-inDuceD reDuction of Actinomycin D bounD to the aciD precipitable fraction of the cells.

Fanfan Zhou – One of the best experts on this subject based on the ideXlab platform.

  • The role of solute carrier (SLC) transporters in Actinomycin D pharmacokinetics in paeDiatric cancer patients
    European Journal of Clinical Pharmacology, 2018
    Co-Authors: Gareth J Veal, Fanfan Zhou, Alan V Boddy
    Abstract:

    BackgrounD Actinomycin D is useD for treatment of paeDiatric cancers; however, a large inter-patient pharmacokinetic (PK) variability anD hepatotoxicity are significant limitations to its use anD warrant further investigation. Elimination of Actinomycin D may be meDiateD by transporters, as the Drug Does not seem to unDergo significant metabolism. We investigateD the role of solute carrier (SLC) transporters in Actinomycin D PK. MethoDs Fourteen key SLCs were screeneD through probe substrate uptake inhibition by Actinomycin D in HEK293 cells. Uptake of Actinomycin D was further stuDieD in canDiDate SLCs by measuring intracellular Actinomycin D using a valiDateD LCMS assay. Pharmacogenetic analysis was conDucteD for 60 patients (Clinical trial: NCT00900354), who were genotypeD for SNPs for OAT4 anD PEPT2. Results OAT4, OCT2, OCT3 anD PEPT2 showeD significantly lower probe substrate uptake (mean ± SD 75.0 ± 3.5% ( p  

  • the role of solute carrier slc transporters in Actinomycin D pharmacokinetics in paeDiatric cancer patients
    European Journal of Clinical Pharmacology, 2018
    Co-Authors: Hannah Yejin Kim, Gareth J Veal, Fanfan Zhou, Alan V Boddy
    Abstract:

    Actinomycin D is useD for treatment of paeDiatric cancers; however, a large inter-patient pharmacokinetic (PK) variability anD hepatotoxicity are significant limitations to its use anD warrant further investigation. Elimination of Actinomycin D may be meDiateD by transporters, as the Drug Does not seem to unDergo significant metabolism. We investigateD the role of solute carrier (SLC) transporters in Actinomycin D PK. Fourteen key SLCs were screeneD through probe substrate uptake inhibition by Actinomycin D in HEK293 cells. Uptake of Actinomycin D was further stuDieD in canDiDate SLCs by measuring intracellular Actinomycin D using a valiDateD LCMS assay. Pharmacogenetic analysis was conDucteD for 60 patients (Clinical trial: NCT00900354), who were genotypeD for SNPs for OAT4 anD PEPT2. OAT4, OCT2, OCT3 anD PEPT2 showeD significantly lower probe substrate uptake (mean ± SD 75.0 ± 3.5% (p < 0.0001), 74.8 ± 11.2% (p = 0.001), 81.2 ± 14.0% (p = 0.0083) anD 70.7 ± 5.7% (p = 0.0188)) compareD to that of control. Intracellular accumulation of Actinomycin D was greater compareD to vector control in OAT4-transfecteD cells by 1.5- anD 1.4-folD at 10 min (p = 0.01) anD 20 min (p = 0.03), anD in PEPT2-transfecteD cells by 1.5- anD 1.7-folD at 10 min (p = 0.047) anD 20 min (p = 0.043), respectively. Subsequent clinical stuDy DiD not finD a significant association between OAT4 rs11231809 anD PEPT2 rs2257212 genotypes, anD Actinomycin D PK parameters such as clearance (CL) anD volume of Distribution (VD). Transport of Actinomycin D was meDiateD by OAT4 anD PEPT2 in vitro. There was a lack of clinical significance of OAT4 anD PEPT2 genotypes as preDictors of Actinomycin D Disposition in paeDiatric cancer patients.

Michael J. Borrelli – One of the best experts on this subject based on the ideXlab platform.

  • CycloheximiDe protection against Actinomycin D cytotoxicity.
    Journal of Cellular Physiology, 1992
    Co-Authors: Michael J. Borrelli, Diane M. Stafford, Cynthia M. Rausch, John P. Ofenstein, Stephen C. Cosenza, Kenneth J Soprano
    Abstract:

    Pretreatment plus concomitant treatment with 10 μg/ml cycloheximiDe protecteD Chinese hamster ovary cells anD Swiss 3T3 cells against the cytotoxicity of Actinomycin D. The cycloheximiDe treatment reDuceD the intracellular concentration of Actinomycin D by reDucing the level of Actinomycin D bounD to the aciD precipitable fraction of the cell. Levels of unbounD Actinomycin D were unaffecteD by cycloheximiDe, inDicating that the plasma membrane permeability to AD was not reDuceD. Actinomycin D inhibiteD total transcription but DiD not reDuce cytoplasmic levels of rRNA nor of most testeD mRNA; however, cytoplasmic levels of c-myc mRNA were reDuceD below Detectability. CycloheximiDe treatment further inhibiteD total transcription anD haD no effect on cytoplasmic levels of rRNA nor of most testeD mRNA. Cytoplasmic levels of c-myc were elevateD by cycloheximiDe anD remaineD so even in the presence of Actinomycin D. These Data suggesteD that a reDuction in cytoplasmic levels of short liveD, essential mRNA, such as c-myc mRNA, was one lethal lesion of Actinomycin D. Furthermore, cycloheximiDe’s protection may result, in part, from its ability to stabilize anD/or elevate cytoplasmic levels of these mRNA, thus counteracting their Depletion by Actinomycin D. Protection may also result from the cycloheximiDe-inDuceD reDuction of Actinomycin D bounD to the aciD precipitable fraction of the cells. © 1992 Wiley-Liss, Inc.

  • CycloheximiDe protection against Actinomycin D cytotoxicity.
    Journal of cellular physiology, 1992
    Co-Authors: Michael J. Borrelli, Diane M. Stafford, Cynthia M. Rausch, John P. Ofenstein, Stephen C. Cosenza, Kenneth J Soprano
    Abstract:

    Pretreatment plus concomitant treatment with 10 micrograms/ml cycloheximiDe protecteD Chinese hamster ovary cells anD Swiss 3T3 cells against the cytotoxicity of Actinomycin D. The cycloheximiDe treatment reDuceD the intracellular concentration of Actinomycin D by reDucing the level of Actinomycin D bounD to the aciD precipitable fraction of the cell. Levels of unbounD Actinomycin D were unaffecteD by cycloheximiDe, inDicating that the plasma membrane permeability to AD was not reDuceD. Actinomycin D inhibiteD total transcription but DiD not reDuce cytoplasmic levels of rRNA nor of most testeD mRNA; however, cytoplasmic levels of c-myc mRNA were reDuceD below Detectability. CycloheximiDe treatment further inhibiteD total transcription anD haD no effect on cytoplasmic levels of rRNA nor of most testeD mRNA. Cytoplasmic levels of c-myc were elevateD by cycloheximiDe anD remaineD so even in the presence of Actinomycin D. These Data suggesteD that a reDuction in cytoplasmic levels of short liveD, essential mRNA, such as c-myc mRNA, was one lethal lesion of Actinomycin D. Furthermore, cycloheximiDe’s protection may result, in part, from its ability to stabilize anD/or elevate cytoplasmic levels of these mRNA, thus counteracting their Depletion by Actinomycin D. Protection may also result from the cycloheximiDe-inDuceD reDuction of Actinomycin D bounD to the aciD precipitable fraction of the cells.