Effects of amsacrine and other DNA-intercalating drugs on nuclear and nucleolar structure in cultured V79 Chinese hamster cells and PtK2 rat kangaroo cells

Abstract

Amsacrine [m-AMSA; 4'-(9-acridinylamino)methanesulfon-m-anisidide] is a synthetic intercalating agent with clinical utility in the treatment of acute leukemias and lymphomas. However, as with other intercalators, its mechanism of action is uncertain. We have examined structural changes induced by amsacrine and other intercalators (actinomycin D, Adriamycin, mitoxantrone, 9-aminoacridine) in cultured Chinese hamster (V79-171b) and rat kangaroo kidney epithelial (PtK2) cells, using light- and electron microscopy with simultaneous assessment of cell survival. During chronic exposure at low concentrations, amsacrine causes cell and nuclear enlargement, lobulation of the nucleus, and nucleolar segregation. Nucleolar segregation was also induced by the other four intercalators. The cytotoxic potency of these drugs, as measured by cell survival after 1-hr exposure, was compared with potency of induction of nucleolar segregation. Relative potencies in the two assays varied by more than 10(4)-fold, with actinomycin D the most effective and amsacrine the least effective inducer of nucleolar segregation relative to cytotoxic potency. Thus, although all five intercalators induced nucleolar segregation with high specificity, this lesion does not correlate with cell killing by these drugs. However, interference with nucleolar function (i.e., ribosomal RNA synthesis) may be responsible for the reversible cytostatic effect observed on chronic exposure to some intercalators (actinomycin D, 9-aminoacridine) at low concentrations.