Alkylformamides as inducers of tumour cell differentiation--a mini-review

The induction of terminal differentiation in tumour cells represents a possible therapeutic strategy for treating cancer. The alkylformamides are 1 group of experimental compounds which have been shown to induce terminal differentiation in human HL-60 leukemia and murine Friend erythroleukemia cells in vitro. Their mechanism of action is unknown. Dimethylformamide has been used as a model inducer in carcinoma and fibroblastic models. Analysis of the relationship between structure and inducing activity of the alkylformamides in vitro reveals that no specificity of structure exists and that their properties as inducers of terminal differentiation extend to related compounds, e.g. the alkylacetamides and alkylureas. This is in contrast to the marked specificity of N-methylformamide (NMF) as an in vivo antitumour agent. The potency of these compounds as inducers of differentiation is predictable and correlated with their molecular weight. High concentrations of NMF are required to induce differentiation in vitro and these concentrations are not achievable in vivo. However, while NMF is unlikely to be a useful inducer in vivo many of its higher MW analogues are very much more potent as inducers in vitro and yet no more toxic (to the host) in vivo. Some of these (e.g. tetramethylurea or 1,3-dimethylurea) may be capable of achieving inducing concentrations in vivo.