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Correlation between the Molecular Weight and Potency of Polar Compounds Which Induce the Differentiation of HL-60 Human Promyelocytic Leukemia Cells¹

Cancer Research Campaign Experimental Chemotherapy Group, Pharmaceutical Sciences Institute, Aston University, Birmingham B4 7ET, United Kingdom

Structure-activity studies of a series of polar organic compounds, including N,N-dimethylformamide, N-methylformamide, and related ureas and acetamides, were performed with regard to their ability to promote the terminal differentiation of the human promyelocytic leukemia cell line HL-60 to granulocyte-like cells. Functional and morphological criteria were used to assess the percentage of differentiated cells which arose from their continuous incubation with different concentrations of each agent over a period of 96 h. All of the alkylformamides, alkylacetamides, and alkylureas tested were found to induce differentiation, regardless of structure. Inspection of the results showed that there was a linear relationship (r = -0.937) between the molecular weight of each compound and the logarithm of the concentration which was required to bring about the differentiation of the greatest number of cells, while viability was generally maintained at >85%. Once established, this relationship was used to predict the potency of several polar solvents which were structurally unrelated to the formamides. For example, methanol, ethanol, and acetone were all inducers of differentiation with a potency predictable from their molecular weight alone. The terminal differentiation induced by all of the compounds was only accomplished by cells which were capable of replication prior to differentiation. At concentrations which prevented a single replication and brought about a fall in cell viability over 96 h, no differentiation was observed. A correlation was observed between the molecular weight of each compound and the logarithm of its concentration to bring about cytotoxicity without differentiation (r = -0.935), and the line was almost parallel to that defining the concentration required for optimal differentiation (slope values of -0.02126 and -0.02288). A poorer (r = -0.6654) correlation was found between the logarithm of the octanol-water partition coefficient and the logarithm of the concentration required for optimal differentiation, when the data for 12 of the polar organic compounds were analyzed. The results suggest that no special structural requirements are necessary for the alkylformamides, -acetamides, -ureas, and related compounds to induce the terminal differentiation of HL-60 cells to granulocyte-like cells, but that the activity of each compound could be predicted from their molecular weight. The concentrations required to induce differentiation were marginally lower than those which were cytostatic or cytotoxic, which suggested that a toxic threat to the cells was sufficient to induce differentiation. Retrospective analysis of a wide variety of compounds which have been reported to induce the differentiation of HL-60 cells revealed that, up to a molecular weight of approximately 400, a significant (P = 0.0182) but poorer correlation (r = -0.665) existed for the relationship between molecular weight and the logarithm of the concentration which induced optimal differentiation.

¹ Supported by Grant SP 1518 from the Cancer Research Campaign.

² Present address: ICRF Medical Oncology Unit, Western General Hospital, Edinburgh EH4 2XU, Scotland.

³ To whom requests for reprints should be addressed.

Received 1/21/86. Revised 6/30/86. Accepted 9/30/86.