The goal ofthis study was to demonstrate that glutathione S-transferase(GST)-π is directly involved in the Intrinsic and acquired resistance of cancer cells to anticancer drugs. To this end, GST-π antisense eDNA was transfected Into the cultured human colon cancer cell line M7609, which expresses an Innately high level of GST-π and shows intrinsic drug resistance, and Into an M7609 strain with acquired resistance to Adriamycin(ADRL;i.e., M7609/ADR cells). The changes in the sensitivity of these transfectants to various anticancer drugs were investigated. The intracel lular concentrations of GST-π in M7609/anti.1 cells and M7609/anti-2 cells, two clones that were established by transfection of GST-π antisense eDNA 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 transfec tents In relation to ADR, cisplatin, melphalan, and etoposide were in creased ∼ 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, S-fluorouradll, and mitomycin C were not significanfly changed. Similarly, the transfection of antisense cDNA Into M7609/ADR cells resulted in the reduction of intra. cellular GST-π concentration (by about half) and an Increased sensitivity to ADR (4.4-fold), but no increase In 5-fluorouradil sensitivity. Thus,GST-π isconsidered 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.

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