N,N'-Hexamethylenebisacetamide (
HMBA) induces transformed cells to differentiate, accompanied by suppression of oncogenicity. Clinical trials have shown that
HMBA can cause positive therapeutic responses in some
cancer patients, but clinical efficacy may be limited, in part, by dose-related toxicity. Potential improvements in efficacy may be accomplished by changes in the chemical structure of inducing agents and by increasing the sensitivity of
tumor cells to inducers of differentiation. We have previously described an approach to improving
tumor cell responsiveness to inducing agents. Transformed cell lines that have acquired low levels of resistance to
vincristine display a markedly increased sensitivity to
HMBA. We now report on a series of hybrid polar/apolar compounds--some of which are as active as
HMBA and several of which are significantly more active than
HMBA in vitro--whose chemical structures make it likely that they have different pharmacokinetics.
Vincristine-resistant murine
erythroleukemia cells also are shown to have marked increased sensitivity to these hybrid polar/apolar compounds. Thus these findings suggest potentially useful strategies for the application of polar/apolar inducers of differentiation to the treatment of
cancers. These studies also provide approaches to further understanding of the biological process of terminal differentiation.