Cultivation of Ehrlich-ascites tumor cells in the presence of N-mustard leads to a selection of cells with a defective choline carrier. As N-mustard employs the choline carrier for transport, this results in reduced drug uptake and in a decrease in drug sensitivity which is specific for N-mustard. Walker carcinoma cells with a stable pleiotropic resistance to a variety of alkylating agents and adriamycin exhibit no evidence for an impaired drug transport and show the same frequency of DNA-interstrand cross-links as the sensitive parental line. Both sensitive and resistant Walker cells exhibit equal capacities for repair of N-mustard induced DNA-interstrand cross-links. The inhibition of histone acetylation by N-mustard, however, was found to be significantly lower in the resistant Walker or Ehrlich cells compared to sensitive counterparts. Although the difference between N-mustard concentrations leading to half maximal inhibition of histone acetylation in sensitive and resistant cells is considerably smaller than the difference between N-mustard doses required for half maximal inhibition of cell proliferation the data suggest that--besides DNA-DNA cross-linking--the inhibition of histone acetylation has to be considered as an important alternative mechanism responsible for the cytotoxic activity of alkylating agents. Inhibition of histone acetylation is not due an accelerated deacetylation and is predominantly expressed in chromatin fractions soluble in 0.1 M NaCl after digestion with micrococcal nuclease.

Oncogenes, onc-gene products and the concept of autonomous self-stimulation of tumor growth by autocrine production of growth factors are discussed with regard to the development of new antitumor agents. The significance of the plasma membrane as an attractive target in tumor chemotherapy is emphasized. Membrane bound enzymes and related reactions which are involved in growth factor dependent regulation of cell proliferation offer new targets for antitumor chemotherapy. Examples demonstrating the antiproliferative effects of phospholipase-C and calmodulin inhibitors are presented. A synergistic effect of these drugs with alkylating agents is observed. Studies devoted to the improvement of alkylating antitumor agents have also led to the plasma-membrane as a particularly suited target. The same may be true for other antitumor agents like anthracyclines and platinum complexes for which evidence exists implicating the involvement of cellular membranes in the mechanism of cytotoxic action.