MODULATION OF THE CYTOSOLIC CA-L-SERINE ANALOGS - RELATION TO THEIR ANTIPROLIFERATIVE ACTION(+ CONCENTRATION BY ALKYLPHOSPHO)

Antiproliferative alkyllysophospholipid (ALP) analogs produced multipl e effects on the cytosolic Ca++ concentration ([Ca++](i)) in an immort alized human breast epithelial cell line (H 184). The addition of smal l concentrations resulted in a short transient [Ca++](i) response. Wit h higher concentrations the transient rise was followed by a sustained increase. Pretreatment of cells with the ALP analogs for two minutes inhibited the transient [Ca++] response. Increases in [Ca++](i) and in hibition of the transient increase were studied in relation to the dos e and structure of several ALP analogs. In a series of alkylphospho-L- serine analogs with different lengths of the alkyl chain we found diff erent dependencies of the stimulatory and inhibitory effects on the do se and the structure. The ability to increase [Ca++](i) is absent with the C-14 and C-15 analogs, is low with the C-16 and high with the C-1 8 analog. With the exception of the C-12 analog, a dose-related inhibi tion was observed with all derivatives but the effective concentration s differed very strongly and the maximal potency was reached with the C-15 and C-16 analogs. The antiproliferative action seems to correlate rather with the potency to inhibit the transient [Ca++](i) response t han with its stimulation.