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 resistance mechanism against these agents. We have evaluated the chemosensitivity of fresh surgical specimens of breast cancer and compared them with their Pgp-expression.


METHODS
The in vitro chemosensitivity of 65 surgical specimens obtained from 63 patients with advanced breast cancer was assessed by the histoculture drug response assay (HDRA) using doxorubicin (DXR), pirarubicin [(2"R)-4'-tetrahydropyranyladriamycin: THP], and epirubicin (EPIR). Breast cancer tissues were plated onto collagen gel matrix and incubated with 15 micrograms of DXR or EPIR, or 17 micrograms of THP per ml for 7 days with MTT assessed at the endpoint. The efficacy of the agents was evaluated by the inhibition index (I.I.) of the optical density detected by ELISA reader.


RESULTS
When 60% or more I.I. was regarded as in vitro sensitive at each cut-off concentration of the drugs, the overall efficacy rates were 60.7%, 48.6%, 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) specimens and the efficacy of anthracyclines was reduced in Pgp-positive breast cancer tissues, although this reduction was low in THP with a statistically significant difference when comparing with DXR and EPIR.


CONCLUSIONS
The present results suggest that THP might partly circumvent the mdr1/PgP-mediated drug resistance mechanism in human breast cancer tissue and would have some different antitumor spectra on breast cancer comparing with DXR and EPIR.
Kubota
T
T
Department of Surgery, School of Medicine, Keio University, Tokyo, Japan. tkubota@mc.med.keio.ac.jp
Furukawa
T
T
Tanino
H
H
Oura
S
S
Murata
H
H
Yuasa
S
S
Morita
K
K
Ueno
J
J
Kozakai
R
R
Yano
T
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015251:Epirubicin / Q000494:pharmacology; D005260:Female; D006801:Humans; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D015251:Epirubicin; D004317:Doxorubicin; C027260:pirarubicin