Tamoxifen circumvents the multidrug resistance in fresh human gastrointestinal cancer cells.
The resistance to doxorubicin (DOX) is mainly due to the effect of P-glycoprotein encoded by the multidrug resistance-1 (mdr1) gene. Tamoxifen (TAM) has been shown to circumvent multidrug resistance in P-glycoprotein-expressing cell lines. In the present study, we clarified the augmentation of DOX sensitivity by TAM using MTT assay in highly purified fresh human tumor cells obtained from 85 cancer patients. Moreover, the correlation between DOX sensitivity and P-glycoprotein expression was assessed by flow cytometry. DOX sensitivity was decreased in proportion to P-glycoprotein expression. The cytotoxicity of DOX was increased by TAM in tumor cells possessing low DOX sensitivity. Moreover, there was a significant correlation between the effect of TAM on cytotoxicity and P-glycoprotein expression. The concentration of DOX in tumor cells was increased in combined exposure of TAM with DOX, compared with the exposure of DOX alone. Thus, TAM might be able to circumvent DOX-resistance for treatment in cancer patients.
Hotta
T
T
Second Department of Surgery, Wakayama Medical School, 27-Shichibancho, Wakayama, 640, Japan.
Tanimura
H
H
Yamaue
H
H
Iwahashi
M
M
Tani
M
M
Tsunoda
T
T
Tamai
M
M
Noguchi
K
K
Mizobata
S
S
Arii
K
K
Terasawa
H
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D004357:Drug Synergism; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D013629:Tamoxifen; D004317:Doxorubicin