PIRARUBICIN MIGHT PARTLY CIRCUMVENT THE P-GLYCOPROTEIN-MEDIATED DRUG-RESISTANCE OF HUMAN BREAST-CANCER TISSUES

Background: Anthracyclines are the first line antitumor agents against breast cancer, and P-glycoprotein (Pgp) is thought to be the main res istance mechanism against these agents. We have evaluated the chemosen sitivity of fresh surgical specimens of breast cancer and compared the m with their Pgp-expression. Materials and Methods: The in vitro chemo sensitivity of 65 surgical specimens obtained from 63 patients with ad vanced breast cancer was assessed by the histoculture drug response as say (HDRA) using doxorubicin (DXR), pirarubicin [(2 '' R)-4'-tetrahydr opyranyladriamycin: THP] and epirubicin (EPIR). Breast cancer tissues were plated onto collagen gel matrix and incubated with 15 mu g of DXR or EPIR or 17 mu g of THP per ml for 7 days with MTT assessed at the endpoint. The efficacy of the agents was evaluated by the inhibition i ndex (I.I.) of the optical density detected by ELISA reader. Results: When 60% or move I.I. was regarded as in vitro sensitive at each cutof f concentration of the drugs, the overall efficacy rates were 60.7%, 4 8.6% and 78.6% for DXR, EPIR, and THP, respectively Fifty-one surgical specimens were evaluated for the immunohistochemical analysis of Pgp and the correlation between the sensitivity to anthracyclines and the expression of Pgp was compared. Pgp was expressed in 23.5% (12/51) spe cimens and the efficacy of anthracyclines was reduced in Pgp-positive breast cancer tissues, although this reduction was low in THP with a s tatistically significant difference when comparing with DXR and EPIR. Conclusion: The present results suggest that THP might partly circumve nt the mdr1/PgP-mediated drug resistance mechanism in human breast can cer tissue and would have some different antitumor spectra on breast c ancer comparing with DXR and EPIR.