The relationship between lipophilic-hydrophilic balance, uptake and anti-bacteriophage lambda activity of...

The uptake by Escherichia coli of a series of bisquaternary experimental anti-tumour agents (quinolinium 4-[p-9(-pyridylamino)phenylcarbamoyl]-aniline-bisalkyl dibromides) has been measured both by association of radiolabelled compounds and their inhibition of the vegetative replication of bacteriophage lambda (after heat inactivation of the phage repressor) as a measure of biologically effective intracellular drug concentration. Uptake of these compounds was correlated with biological effect, and was a function of both incubation temperature and the lipophilic-hydrophilic balance of the compound. At 30 degrees C uptake was drug concentration-dependent and was not readily reversible. No saturation of uptake was apparent over the concentration range tested. Preliminary experiments indicated that time-dependent drug uptake was also related to growth inhibition in cultured L1210 murine leukaemia cells. These results are consistent with the hypothesis that uptake occurs by diffusion across the plasma membrane followed by strong binding to cell constituents such as DNA. The approximate range of uptake of the most active compounds, using an external drug concentration of 1 microM, are 100 and 2400 molecules/s respectively for bacteria and murine leukemia cells. For bacteria, the uptake of approx. 2 X 10(5) molecules of drug/cell inhibits the yield of phage lambda by 90%.