Transfection of glutathione S-transferase (GST)-pi antisense complementary DNA increases the sensitivity of a colon cancer cell line to adriamycin, cisplatin, melphalan, and etoposide.
The goal of this study was to demonstrate that glutathione S-transferase (GST)-pi is directly involved in the intrinsic and acquired resistance of cancer cells to anticancer drugs. To this end, GST-pi antisense cDNA was transfected into the cultured human colon cancer cell line M7609, which expresses an innately high level of GST-pi and shows intrinsic drug resistance, and into an M7609 strain with acquired resistance to Adriamycin (ADR;i.e., M7609/ADR cells). The changes in the sensitivity of these transfectants to various anticancer drugs were investigated. The intracellular concentrations of GST-pi in M7609/anti-1 cells and M7609/anti-2 cells, two clones that were established by transfection of GST-pi antisense cDNA into M7609 cells, were decreased to approximately half of those detected in the parent cells (M7609) and in the control cells transfected with vector alone (M7609/pLJ). The sensitivities of the antisense transfectants in relation to ADR, cisplatin, melphalan, and etoposide were increased -3.3-fold, 2.3-fold, 2.2-fold, and 2.1-fold, respectively, compared with those of M7609 and M7609/pLJ. On the other hand, the sensitivities of the antisense transfectants to Taxol, vincristine, 5-fluorouracil, and mitomycin C were not significantly changed. Similarly, the transfection of antisense cDNA into M7609/ADR cells resulted in the reduction of intracellular GST-pi concentration (by about half) and an increased sensitivity to ADR (4.4-fold), but no increase in 5-fluorouracil sensitivity. Thus, GST-pi is considered to be a multidrug resistance factor that is responsible for both the intrinsic and acquired resistance of cancer cells to anticancer drugs such as ADR, cisplatin, melphalan, and etoposide.
Ban
N
N
Department of Internal Medicine, Sapporo Medical University, Japan.
Takahashi
Y
Y
Takayama
T
T
Kura
T
T
Katahira
T
T
Sakamaki
S
S
Niitsu
Y
Y
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D015139:Blotting, Southern; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D016373:DNA, Antisense / Q000008:administration & dosage* / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D016373:DNA, Antisense; D007527:Isoenzymes; D005982:Glutathione Transferase