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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

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