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Differentiation of WEHI-3B D⁺ Monomyelocytic Leukemia Cells by Retinoic Acid and Aclacinomycin A¹

Departments of Pharmacology and Surgery and Developmental Therapeutics Program, Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06510

WEHI-3B D⁺ monomyelocytic leukemia cells were induced to differentiate to mature granulocytes when treated with either 30 nM aclacinomycin A or 7 µM retinoic acid. Differentiation was assessed by the appearance of mature granulocytic phenotypes, as measured by the ability to reduce nitro blue tetrazolium, morphological changes, an increase in cell surface Fc receptors, as well as the loss of proliferative capacity. Maximum differentiation occurred 3 days after drug exposure. Analysis of DNA histograms of treated cells indicated that cells accumulated in the G₁ phase of the cell cycle after 8 h of exposure to either inducer, with maximum accumulation occurring by 20 h; this arrest was observed prior to the phenotypic appearance of mature cells. The minimum interval of time necessary to commit cells to a differentiation pathway, which was less than one doubling time (9.2 h), closely paralleled the initial accumulation of cells in the G₁ phase of the cell cycle. Since drug exposure for more than one cell division was required for maximum differentiation, the observed kinetics of maturation is consistent with a stochastic model. These studies support the idea that this cell line would be a particularly good model for extrapolation of findings with differentiating agents in culture to therapeutic monitoring in animals, since WEHI-3B D⁺ leukemia cells can be readily propagated in vivo in BALB/c mice.

¹ This research was supported in part by USPHS Grant CA-02817 from the National Cancer Institute.

² To whom requests for reprints should be addressed.

Received 7/ 2/85. Revised 11/19/85. Accepted 11/22/85.