MOLECULAR AND CELLULAR EFFECTS OF HEXADECYLPHOSPHOCHOLINE (MILTEFOSINE) IN HUMAN MYELOID LEUKEMIC-CELL LINES

The molecular and cellular effects of the anti-neoplastic alkylphospho lipid hexadecylphosphocholine (Miltefosine, MIL) on parameters associa ted with growth and differentiation of human myeloid leukaemic cell li nes U937, KG1 and KG1a were investigated. On a cellular level, MIL has dose-dependent differentiation-inducing, growth-promoting and cytotox ic activities exemplified by induction of respiratory burst activity, stimulation of interleukin-3 (IL-3)/granulocyte-macrophage colony stim ulating factor (GM-CSF)-dependent growth of the KG1 cell line in soft agar culture, inhibition of cellular net growth and finally cell death . By northern blot analysis, transcription of functional receptors for IL-3, GM-CSF, G-CSF and FcRI were studied. It was shown that MIL has stimulatory activity on IL-3 and GML-CSF receptor gene transcription. In addition, the transcription of proliferation- and differentiation-a ssociated proteins, namely histone subtypes, c-myc and NF-kappa B p50, were studied. MIL suppressed c-myc and enhanced NF-kappa B p50 transc ription in the U937 cell line, comparable to the well-characterised di fferentiation-inducing phorbolester 12-O-tetradecanoylphorbol-13-aceta te (TPA). We conclude that the interaction of MIL with its molecular t arget(s) in myeloid cells induces molecular and cellular effects assoc iated with induction of differentiation, distinct from its cytotoxic a ctivity.