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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

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  1. Your Logo Here CYTOCHROME P450 3A AS A MEDIATOROF CHEMOTHERAPY RESISTANCEIN PATIENTSWITH SOFT TISSUE SARCOMA

  2. DISEASE-FREE SURVIVALBY IFOSFAMIDE DOSE Worden, JCO (2005)

  3. ERYTHROMYCIN BREATH TEST • [14C N-methyl] erythromycin • CYP3A metabolizes erythromycin, liberating a carbon atom as CO2 • Measures in vivo activity of CYP3A Dosemean %range % 6 2.4 0.87-4.32 12 2.2 0.43-4.17

  4. CYTOCHROME P450 CYP3A Normal Liver • Most abundant p450 in liver • Composed of four family members • 3A4 • 3A5 • 3A7 • 3A43 • Responsible for metabolism of: • Ifosfamide • Vinblastine • Doxorubicin • Etoposide Modified after Furlanut and Franceschi (2003) Oncology 65(Suppl 2): 2-6.

  5. ERMBT OVERALL SURVIVAL P value 0.0992 P value 0.0526

  6. CYP3A QIF AND ERMBT r2 5.84 x 10-6

  7. 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

  8. QIF RELIABILITY STUDIES INTRA-ASSAY VARIABILITY INTER-ASSAY VARIABILITY

  9. 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

  10. QIF CYP3A AND TUMOR HISTOLOGY

  11. TUMOR CYP3A QIF AND SURVIVAL P value 0.0353*

  12. TUMOR CYP3A QIF AND SURVIVAL P value 0.0415*

  13. 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

  14. 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 ACKNOWLEGMENTS

  15. Your Logo Here CYTOCHROME P450 3A AS A MEDIATOROF CHEMOTHERAPY RESISTANCEIN PATIENTSWITH SOFT TISSUE SARCOMA

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