Because solid growing tumors often show pronounced hypoxia and extracellular acidosis, we analysed the impact of acidosis on cellular content and cytotoxicity of the cytostatic daunoru-bicin in AT1 cells. Cells were exposed to an acidic extracellu-lar environment (pH 6.6) alone for 3h and for additional 3h in combination with daunorubicin. Protein amount and daunoru- bicin content was determined directly after exposure and after 48h. Acidosis substantially reduced cytotoxicity and cell con-tent of daunorubicin. Inhibition of protein synthesis had no effect on the respective cellular daunorubicin content. Acidosis increased the activity of the drug efflux pump pGP and more-over activated both ERK1/2 and p38 in AT1 cells. Inhibition of ERK1/2 and p38 totally abolished the growth inhibitory effect of acidosis, which was associated with an increase of the daunorubicin content to control levels. We therefore hypothesize that in AT1 cells extracellullar acidosis activates pGP via ERK1/2 and p38, leading to reduced cellular daunorubicin accumulation. Thereby the susceptibility of the tumor cells to daunorubicin decreases. These findings may explain the reduced cytotoxicity of chemo- therapeutic agents in acidic tumors and gives first evidence of the signalling mechanisms involved.

(supported by the Deutsche Krebshilfe)