Kinetic Response of Cultured Chinese Hamster Cells to Treatment With 4′-[(9-Acridinyl-amino] methanesulphon-m-anisidide-HCl2

Abstract

4′-[(9-Acridinyl)-amino]methanesulphon-m-anisidide- HCl (MAC) (NSC-141549) was examined for effects on survival and cell-cycle progression in exponentially growing (cycling) populations of line CHO Chinese hamster cells and in isoleucine-deficient G₁-arrested (noncycling) cells. Cell analysis involved flow microfluorometry, [³H]thymidine autoradiography, and cell enumeration. Noncycling cells were approximately two to four times more resistant to the toxic effects of MAC, although at high concentrations (i.e., Δ2 μg/ml), noncycling cells appeared to be as sensitive as cycling cells. Noncycling cells treated with MAC prior to return to cycle traversed through G, and S at a nearly normal rate and suffered only a slight delay (≈2 hr) in progressing through G₂ and mitosis. In contrast, in cycling cell populations treated with MAC and under conditions yielding similar survival levels, the cells initially in Sand G₂ were grossly delayed in their capacity for normal progression, leading to a transitory (≈8 hr) accumulation of cells in S, followed at later times by arrest in G₂; a subpopulation of cells initially In G₁ progressed through G₁ and S at a nearly normal rate and then appeared to be delayed for only 2 hours in traversing through G₂ and mitosis. A limited degree of unequal distribution of chromosome fragments to daughter cells at mitosis and a high degree of polyploidization were induced in cycling cell populations receiving MAC. Cycling cells exposed to MAC exhibited a terminal point of inhibition of traverse capacity situated 57 minutes prior to prophase. On the basis of the generally similar kinetic responses observed with MAC and adriamycin (ADR), we would expect MAC to exhibit many biochemical properties in common with ADR.