Structure-activity relationships of alkylphosphocholine derivatives: antineoplastic action on brain tumor cell lines in vitro.

Erucylphosphocholine (ErPC) is a promising candidate for the treatment of human brain tumors. The aim of the present study was to investigate whether structural modifications of ErPC would improve its antineoplastic activity in vitro. The novel alkylphosphocholine (APC) derivatives docosenyl-( cis-10,11)-phosphocholine, tricosenyl-( cis-12,13)-phosphocholine, heneicosenyl-( cis-12,13)-phosphocholine and erucyl- N, N, N-trimethylpropanolaminophosphate all reduced cell growth and viability of rat and human astrocytoma/glioblastoma (AC/GBM) cell lines (C6, T98G, U87MG, A172) and had improved antineoplastic activity when compared to the prototypical APC hexadecylphosphocholine (HePC). However, the four cell lines differed in their sensitivity to the APC derivatives. A172 cells were most sensitive to their cytostatic action and T98G cells to their cytotoxic action. The LC(50) values for T98G cells after a 72-h exposure to the novel derivatives varied between 25 and 54 microM compared to 45+/-8.1 microM for ErPC. Complete killing of T98G cells was obtained with all derivatives at 90 microM. Structural modifications of the chain length of the alcohol moiety as well as changing the position of the double bond within the alkyl chain improved cytotoxicity of the APC in C6 and A172 cells and to a lesser extent in T98G cells, whereas U87MG cells showed almost similar sensitivities to the novel drugs and ErPC. Increasing the distance between the phosphorus and nitrogen atoms within the polar phosphocholine group did not alter antineoplastic activity but modified physicochemical characteristics, e.g. increased the solubility in water. In a similar manner to ErPC, all derivatives induced growth arrest in the G(2)/M phase of the cell cycle and apoptotic cell death. Importantly, none of the derivatives showed hemolytic activity. As there was no clear superiority of any of the novel derivatives, ErPC remains the leading APC derivative for future clinical trials in brain tumor chemotherapy.