Structure‐activity relationships of four anti‐cancer alkylphosphocholine derivatives In Vitro and In Vivo

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Abstract
This study was carried out to investigate whether structureactivity relationships of alkylphosphocholines, a new group of anti‐neoplastic agents, which had been detected in methylnitrosourea(MNU)‐induced rat mammary carcinoma, can be transferred to in vitro systems. Therefore, the anti‐neoplastic activity of 4 alkylphosphocholines (APCs) was compared in 6 tumor cell lines in vitro and in MNU‐induced rat mammary carcinoma in vivo. The in vitro system consisted of 2 rat mammary‐carcinoma‐derived cell lines (I/C2 and I/C32), as well as 2 human mammary‐gland (MDA‐MB‐231 and MCF‐7)‐and gastrointestinal tract (HT‐29 and KB)‐derived tumor cell lines. As assessed by both cell counting and MTT‐assay, the ranking of concentrations effecting 50% growth inhibition (IC50) was parallel in all cell lines for octadecylphosphocholine (18:0‐PC), octadecenyl‐(trans‐9.IO)‐phosphocholine (t‐ 18:1‐PC) and octadecenyl‐(cis‐9.10)‐phosphocholine (c‐ 18:1‐PC). Only hexa‐decylphosphocholine (16:0‐PC) differed in its activity, being least active in I/C2, I/C32 and MDA‐MB‐231 cells, moderately active in KB and MCF‐7 cells, and most active in HT‐29 cells. The IC50 concentrations of APCs in the 2 rat mammary carcinoma cell lines significantly correlated with dosages effecting a 50% tumor growth delay in vivo. Remarkably, the 2 gastrointestinal cell lines were more sensitive to APC exposure than the mammary‐carcinoma cell lines. In all cell lines except KB cells, growth‐stimulation effects were seen in the concentration range preceding the anti‐proliferative activity; in vivo, however, no accelerated cancer growth was observed. The in vitro system failed to describe the superior therapeutic ratio of c‐18:1‐PC, as assessed in vivo, because it does not take the relative sensitivity of tumor vs. normal cells into account. Complementary in vivo trials are therefore indispensable for a final evaluation. Comparison of the 2 in vitro assays shows good agreement of the interrelationship of IC50 values, those obtained by MTT assay being on average 25% higher than those obtained from cell counting.