MALIGNANT PHENOTYPE CORRELATING WITH DRUG-RESISTANCE IN 2 HUMAN NEUROBLASTOMA CELL-LINES

The main cause for the failure of chemotherapeutic treatment of advanced cancer probably lies in the emergence of drug resistant clones. In the present study we compared the sensitivity to adriamycin (ADR) and the capacity of ADR uptake in two human neuroblastoma cell lines differing in properties relevant to metastatic potential, the GP(2) and MB, of low- and high-malignancy phenotype, respectively. Examination of the ADR effect on in vitro proliferative capacity of the two cell lines revealed a higher sensitivity of GP(2) as compared to the MB variant. Intracellular ADR accumulation was determined by fluorocytometry, spectrofluorometry and fluorescence microscopy. According to the three methods, the GP(2) line cells, representing a low-malignancy phenotype, had a higher uptake ability than the MB cells, possessing a phenotype of higher aggressiveness. The quantitative determination revealed that over a broad range of ADR concentrations, the GP(2) cells accumulated 2-3.5 folds the amount of cytotoxic agent penetrating the MB cells. The FACS analysis showed that the cell population of each of the variants consisted of two subpopulations varying in their ability to accumulate ADR. In the GP(2) line the high permeability subpopulation represented nearly half of the total cell population, whereas in the MB line this subpopulation represented a minority. The correlation observed between ADR uptake capacity and sensitivity to the cytotoxic agent, as evidenced by its effect on proliferative capacity, suggests that the resistance of the MB cells is due to a P-G-P modification-related mechanism.