your logo here
DESCRIPTION
Your Logo Here. C YTOCHROME P450 3A AS A M EDIATOR OF C HEMOTHERAPY R ESISTANCE IN P ATIENTS WITH S OFT T ISSUE S ARCOMA. D ISEASE -F REE S URVIVAL BY I FOSFAMIDE D OSE. Worden, JCO (2005). E RYTHROMYCIN B REATH T EST. [ 14 C N-methyl] erythromycin - PowerPoint PPT PresentationTRANSCRIPT
![Page 1: Your Logo Here](https://reader035.vdocument.in/reader035/viewer/2022062808/5681540f550346895dc20d14/html5/thumbnails/1.jpg)
Your Logo Here
CYTOCHROME P450 3A AS A MEDIATOR OF CHEMOTHERAPY RESISTANCE IN PATIENTS
WITH SOFT TISSUE SARCOMA
CYTOCHROME P450 3A AS A MEDIATOR OF CHEMOTHERAPY RESISTANCE IN PATIENTS
WITH SOFT TISSUE SARCOMA
![Page 2: Your Logo Here](https://reader035.vdocument.in/reader035/viewer/2022062808/5681540f550346895dc20d14/html5/thumbnails/2.jpg)
DISEASE-FREE SURVIVAL BY IFOSFAMIDE DOSE
Worden, JCO (2005)
![Page 3: Your Logo Here](https://reader035.vdocument.in/reader035/viewer/2022062808/5681540f550346895dc20d14/html5/thumbnails/3.jpg)
ERYTHROMYCIN BREATH TEST
• [14C N-methyl] erythromycin
• CYP3A metabolizes erythromycin, liberating a carbon atom as CO2
• Measures in vivo activity of CYP3A
Dose mean % range % 6 2.4 0.87-4.32 12 2.2 0.43-4.17
![Page 4: Your Logo Here](https://reader035.vdocument.in/reader035/viewer/2022062808/5681540f550346895dc20d14/html5/thumbnails/4.jpg)
CYTOCHROME P450 CYP3A
• Most abundant p450 in liver• Composed of four family members
– 3A4– 3A5– 3A7– 3A43
• Responsible for metabolism of:– Ifosfamide– Vinblastine– Doxorubicin– Etoposide
Normal Liver
Modified after Furlanut and Franceschi (2003) Oncology 65(Suppl 2): 2-6.
![Page 5: Your Logo Here](https://reader035.vdocument.in/reader035/viewer/2022062808/5681540f550346895dc20d14/html5/thumbnails/5.jpg)
ERMBT OVERALL SURVIVAL
P value 0.0992 P value 0.0526
![Page 6: Your Logo Here](https://reader035.vdocument.in/reader035/viewer/2022062808/5681540f550346895dc20d14/html5/thumbnails/6.jpg)
CYP3A QIF AND ERMBT
r2 5.84 x 10-6
![Page 7: Your Logo Here](https://reader035.vdocument.in/reader035/viewer/2022062808/5681540f550346895dc20d14/html5/thumbnails/7.jpg)
QUANTITATIVE IMMUNOFLUORESCENCE (QIF)
• Modification of Indirect IF method• Diminish auto fluorescence with
glycine/PPD• Antibody labeled with Fluor 568• Nuclei labeled with Syto16• Fluorescence analyzed by Mercury
lamp with appropriate filter• Results expressed as F/nuclei
![Page 8: Your Logo Here](https://reader035.vdocument.in/reader035/viewer/2022062808/5681540f550346895dc20d14/html5/thumbnails/8.jpg)
QIF RELIABILITY STUDIES
INTER-ASSAY VARIABILITYINTRA-ASSAY VARIABILITY
![Page 9: Your Logo Here](https://reader035.vdocument.in/reader035/viewer/2022062808/5681540f550346895dc20d14/html5/thumbnails/9.jpg)
BIOLOGICAL STUDIES
• 60/79 patients with FFPE tissue available for study– TMA made
• 19 patients with multiple specimens
• 45/79 patients DNA extracted from FFPE tissue for SNP analysis
![Page 10: Your Logo Here](https://reader035.vdocument.in/reader035/viewer/2022062808/5681540f550346895dc20d14/html5/thumbnails/10.jpg)
QIF CYP3A AND TUMOR HISTOLOGY
![Page 11: Your Logo Here](https://reader035.vdocument.in/reader035/viewer/2022062808/5681540f550346895dc20d14/html5/thumbnails/11.jpg)
TUMOR CYP3A QIF AND SURVIVAL
P value 0.0353*
![Page 12: Your Logo Here](https://reader035.vdocument.in/reader035/viewer/2022062808/5681540f550346895dc20d14/html5/thumbnails/12.jpg)
TUMOR CYP3A QIF AND SURVIVAL
P value 0.0415*
![Page 13: Your Logo Here](https://reader035.vdocument.in/reader035/viewer/2022062808/5681540f550346895dc20d14/html5/thumbnails/13.jpg)
• Decreased ERMBT are suggestive of poorer prognosis.
• Elevated tumor CYP3A protein levels are associated with poor survival.
• No correlations with CYP3A4 or CYP3A5 SNPs.• Prospectively studying patients for CYP3A levels
in new clinical trial.• Examining the role of CYP3A gene induction in
cell lines.
CONCLUSIONS
![Page 14: Your Logo Here](https://reader035.vdocument.in/reader035/viewer/2022062808/5681540f550346895dc20d14/html5/thumbnails/14.jpg)
ACKNOWLEGMENTS
• Larry BAKER• Mark ZALUPSKI• Tom GIORDANO• Sybil BIERMANN• Vernon SONDAK• Rashmi CHUGH• Walther Cancer Research Foundation• Robert Urich Sarcoma Fund• Staff and Patients at University of Michigan
![Page 15: Your Logo Here](https://reader035.vdocument.in/reader035/viewer/2022062808/5681540f550346895dc20d14/html5/thumbnails/15.jpg)
Your Logo Here
CYTOCHROME P450 3A AS A MEDIATOR OF CHEMOTHERAPY RESISTANCE IN PATIENTS
WITH SOFT TISSUE SARCOMA
CYTOCHROME P450 3A AS A MEDIATOR OF CHEMOTHERAPY RESISTANCE IN PATIENTS
WITH SOFT TISSUE SARCOMA