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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

DISEASE-FREE SURVIVAL BY IFOSFAMIDE DOSE

Worden, JCO (2005)

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

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.

ERMBT OVERALL SURVIVAL

P value 0.0992 P value 0.0526

CYP3A QIF AND ERMBT

r2 5.84 x 10-6

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

QIF RELIABILITY STUDIES

INTER-ASSAY VARIABILITYINTRA-ASSAY VARIABILITY

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

QIF CYP3A AND TUMOR HISTOLOGY

TUMOR CYP3A QIF AND SURVIVAL

P value 0.0353*

TUMOR CYP3A QIF AND SURVIVAL

P value 0.0415*

• 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

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

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