Triple combination of retinoic acid plus actinomycin D plus dimethylformamide induces differentiation of human acute myeloid leukaemic blasts in primary culture

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Abstract
Differentiation induction therapy provides an alternative for treatment of acute myeloid leukaemia (AML) patients who are either unsuitable for or unresponsive to conventional cytotoxic chemotherapy. The effect of a triple combination of retinoic acid (RA) + actinomycin D (Act-D) + dimethylformamide (DMF) on differentiation of blasts from 24 AML patients was studied. Nonadherent mononuclear cells were seeded at a concentration of 5 × 105 cells/ml in 24-well tissue-culture plates containing RPMI 1640 culture medium with 20% fetal calf serum, 10% autologous serum and 10% 5637-conditioned medium and incubated with 10−6 M retinoic acid, 5 nM actinomycin D and/or 100 mM dimethylformamide alone and in combination with each other for 6 days at 37° C in a humidified incubator and an atmosphere containing 5% CO2. The triple combination of 10−6 M retinoic acid + 5 nM actinomycin D + 100 mM dimethylformamide induced 90% of the blasts from 22 of the 24 AML patients to differentiate. The combination ofN-methylformamide (a compound similar to dimethylformamide) with cyclophosphamide significantly increased the in vivo activity with no concomitant increase in its reversible hepatotoxicity. Since several polar compounds related to dimethylformamide, e.g. hexamethylene bisacetamide andN-methylformamide, are currently undergoing phase II clinical trials, it may be feasible to combine one of these with retinoic acid and/or actinomycin D in the treatment of AML patients.

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