Effect of a membrane-active agent on uptake of adriamycin in Lewis lung carcinoma cells derived from 'primary' and 'metastatic' growths.

The treatment of metastatic growth still constitutes a challenge for cancer research. Tumor progression is often accompanied by a loss in sensitivity to previously efficient drugs. Decreased intracellular accumulation of cytotoxic agents is probably the major reason for drug resistance, although other mechanisms have also been described. Properties of the cell membrane have been shown to determine the metastatic phenotype. This cellular organelle is also responsible for the multiple drug resistance phenomenon. Membrane-active agents may increase cell permeability to drugs, counteracting thereby drug resistance. In the present study the effect of the nonionic detergent Tween 80 on sensitivity to adriamycin (ADR) of cells derived from Lewis lung carcinoma 'primary tumors' (PT)-the local growth following subcutaneous inoculation - and 'metastatic tumors' (MT) - lung tumors which develop following intravenous injection - was compared. Flow cytometry analysis demonstrated several differences between cells derived from the PT and the MT: (1) single ADR treatment showed that MT cells possessed a lower percentage of a high ADR permeability subpopulation than PT cells; (2) a dose-dependent shift to a higher ADR accumulating population was seen in the presence of Tween 80 for both cell types. However, the increase in percentage of high ADR permeability cells was more pronounced in MT (up to x4.7) than in PT (up to x1.3) cells. This differential effect of the membrane-acting agent was evident at various ADR (10-50 micrograms) and Tween 80 (0.1-0.4%) concentrations. The present results corroborate previous data obtained in our group in another tumor progression model, AKR lymphoma.