The authors established five cell lines from a human head and neck tumor. The five cell lines (HC-2, HC-3, HC-4, HC-7, and HC-9) exhibited different sensitivities to Adriamycin, cisplatin, bleomycin, 5- fluorouracil, vincristine, and daunomycin. The Dw was 200 ng/ml Adriamycin (doxorubicin) for HC-7 and 45 ng/ml for HC-2. At the inception of long-term culture (11 months) in the absence of any drug, the sensitivity to Adriamycin of HC-7-5 (subcloned from HC-7) was 3.4 times greater than that of HC-2-6 (subcloned from HC-2); by 11 months, it decreased to 1.6 times that of HC-2-6. The cytocidal action of Adriamycin on HC-2-6 and HC-7-5 was potentiated when Adriamycin was combined with verapamil or cepharanthine. Cepharanthine also potentiated daunomycin and vincristine (VCR) against HC-2-6 and HC-7-5 cells, and it almost completely overcame drug-resistance to daunomycin and vincristine in HC-7-5/VCR, a multidrug-resistant variant isolated after long exposure to vincristine of HC-7-5 cells in culture. The cellular accumulation of [3H)-daunomycin by HC-7-5 cells was about 70% that of HC-2-6 cells. By Northern blot analysis, using a multidrug-resistance gene (mdr-I) probe, neither HC-2-6 nor HC-7-5 expressed the mdr-2 gene, but HC-7-5IVCR or other multidrug-resistant variants showed active expression of the mdr-I gene. Differential sensitivities among the five cell lines to 5-fluorouraci1, cisplatinum, and bleomycin appear to be mediated through other mechanism beside the mdr-I gene.
Cancer 63:675-681, 1989.
EMISSION INDUCED BY anti-cancer agents such as R Adriamycin (doxorubicin) or vincristine is attributable to the action of the anticancer agents on drug sensitive cell populations in the tumor. However, when relapse occurs, the tumor may no longer respond to drug therapy. Therefore, acquired drug resistance is a serious problem in cancer chemotherapy.'32 In the course of chemotherapy, the drug-sensitive tumor cell population may be eliminated, leaving resistant clones to proliferate. An alternative explanation for drug-resistant tumors is the "pharmacologic hideout"' of tumor cells or the appearance of large number of tumor cells at the GO cell cycle state.