Nine new platelet activating factor (PAF) antagonists from 4 different chemical classes (thiopyrimidines: SDZ 59-015; thioimidazolines: SDZ 61-813; imidazoisoquinolines: SDZ 62-434, SDZ 62-759, SDZ 63-135, SDZ 63-596; and imidazopiperidines: SDZ 61-638, SDZ 62-293, SDZ 62-694) have been tested for cytostatic/antiproliferative ([3H]thymidine uptake) and cytotoxic (trypan blue dye exclusion) activity in neoplastic human cell lines of different histology in vitro. The antiproliferative activity of 3 of the 9 PAF antagonists (SDZ 61-638, SDZ 61-813, SDZ 62-694) was not stable after freezing and thawing. SDZ 59-015 showed only minor cytotoxic or antiproliferative effects in a dose range of 2–40 μm after 24, 48, and 72 h of incubation. SDZ 62-434 showed varying activity. There were no significant differences between the activities of the other 3 PAF antagonists from the imidazoisoquinoline class, which showed drug concentrations inhibiting 50% of the activity studied (IC50) and drug concentrations yielding a 50% decrease of trypan blue dye exclusion (LC50) of ≤20 μm at ≥48 h, even in the K-562 cell line, which is known to be rather resistant for a variety of cytotoxic drugs related to PAF. SDZ 62-293 showed the best antineoplastic properties with IC50 and LC50 values ≤10 μm at ≥48 h including K-562. SDZ 62-434, SDZ 62-759, SDZ 63-135, SDZ 63-596, and SDZ 62-293 have been further tested in a human tumor cloning assay in 5 cell lines. Colony formation was reproducibly suppressed to <30% of the controls only by SDZ 63-135 (≤40 μm) and SDZ 62-293 (≤20 μm) during continuous exposure. There was no correlation between the IC50 values for the antiproliferative activity of the test compounds and their IC50 values for PAF-induced human platelet aggregation. Furthermore, the antiproliferative activity of the most active compound, SDZ 62-293, could not be antagonized by preincubation with the specific PAF antagonists WEB 2170 or WEB 2086 or PAF itself in noncytotoxic doses. In addition, since we were not able to find a correlation between the presence of PAF specific binding sites on neoplastic cells and their respective sensitivity for the cytotoxic effects of the PAF antagonists tested, binding to PAF specific binding sites does not seem to be a prerequisite for the cytotoxic/antiproliferative activity of these test compounds. This study shows antineoplastic activity of some PAF antagonists in vitro and we recommend some of these drugs for further investigation as experimental drugs in cancer therapy.

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This work was supported by Grant Be 822/2-6 from Deutsche Forschungsgemeinschaft and by Sandoz Research Institute, East Hanover, NJ.

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