Alkylphosphocholine - eine neue Klasse von Antitumormitteln Untersuchungen zum biochemischen Wirkungsmechanismus

Alkylphosphocholines (APC) represent a new class of anticancer drugs. Although some compounds of this group are already used for tumor therapy (e.g. hexadecylphosphocholine, HePC), not much is known about their molecular mechanisms of anticancerogenic action. HePC is approved for topical treatment of skin metastases of breast cancer, but systemic application is not possible due to gastro-intestinal side effects. Therefore, new APC compounds were synthesized with the aim to reduce the side effects of HePC while preserving the antineoplastic activities. In the present study, the toxic effects of eight new APC compounds on in vitro cell culture systems of human tumor cells were investigated. Three of the new APC showed higher toxic potency than HePC towards HL-60 leukemia cells. The most active compound was R-1-O-phosphocholine-2-N-acetyl-octadecane (R-N-acetyl), with which further studies were mainly carried out. The uptake of R-N-acetyl by tumor cells was slow and dependent on the content of foetal calf serum in the culture media. R-N-acetyl was metabolically stable and degradation was only marginal. The effect of APC on intracellular signal transduction was further specified. It was demonstrated that APC activate the Ras/MAP kinase cascade via a G-protein coupled mechanism. The EGF-receptor was engaged in the activation of the MAP kinase ERK in MDA-MB-468 mammary carcinoma cells. Furthermore, APC induced concentration-dependent a short, transient and receptor-mediated rise in cytosolic free calcium. (orig.)Available from TIB Hannover: ZA 5141(6369) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman