THE ACTION OF THE DNA INTERCALATING AGENTS 4'-(9-ACRIDINYLAMINO) METHANESULPHON-M-ANISIDIDE AND 1,4-BIS(BUTYLAMINO) BENZO[G]PHTHALAZINE IN U-937 HUMAN PROMONOCYTIC CELLS - RELATIONSHIP BETWEEN CELL-CYCLE AND DIFFERENTIATION

The action of two structurally related DNA intercalating agents has be en studied and compared, namely 4'-(9-acridinylamino) methanesulphon-m -anisidide (amsacrine, mAMSA) and 1,4-bis(butylamino)benzo[g]phthalazi ne (ABP) on the cell cycle and differentiation of U-937 human promonoc ytic leukemia cells. mAMSA (0.1 mu M) and ABP (4 mu M) reduced the pro liferation activity to a similar extent and caused little cell mortali ty. At these subcytotoxic concentrations mAMSA induced the cells to ac cumulate at the G(2) phase of the cycle, while cycle inhibition provok ed by ABP was not phase specific. In addition, mAMSA caused an increas e in the cell mass while ABP provoked cell shrinkage. This was consist ent with the fact that ABP considerably inhibited protein synthesis, w hile mAMSA did not significantly affect this activity. SDS/K(+)DNA pre cipitation assays indicated that mAMSA, but not ABP, stimulated protei n-DNA covalent complex formation. Finally, it was found that mAMSA, bu t not ABP, elicited the expression of differentiation markers, namely nitroblue tetrazolium reduction, activation of vimentin and leukocyte integrin (CD11b/CD18 and CD11c/CD18) expression, and downregulation of c-myc expression. The DNA intercalators doxorubicin and mitoxantrone, which like mAMSA induced the cells to accumulate at the G(2) phase an d increased the cell mass, induced the expression of differentiation m arkers. In contrast, the intercalators aclarubicin and caffeine and th e non-intercalator novobiocin, which produced minor alterations on cel l-cycle distribution and caused cell shrinkage, did not significantly elicit differentiation. These results support the conclusion that diff erentiation of myeloid leukemia cells by cytostatic drugs depends on t he perturbations of the cell cycle, leading to disproportionate increa ses in cell mass.