HUMAN TUMOR-CELL GROWTH MODULATORY EFFECTS OF THE AEBS HIC-BINDING DRUGS USED AS SINGLE AGENTS AND IN COMBINATION WITH A NOVEL AMPHIBIAN OOCYTE RNASE/

A novel amphibian oocyte RNase, ONCONASE(R) (ONC), has been previously shown to have synergistic tumor cell growth inhibitory activity when combined with tamoxifen (TMX) and/or trifluoperazine (TFP) in human AS PC-1 pancreatic and A-549 lung carcinoma cells, respectively. It has r ecently been reported that several drugs known to bind to the intracel lular antiestrogen binding site (AEBS)/histamine (H(IC)) receptors, in cluding tricyclic (amitriptyline, AMT) and non-tricyclic (fluoxetine, FLX) antidepressants, TMX, phenothiazines and the prototype H(IC)-bind er DPPE, can stimulate the in vitro and in vivo growth of rodent tumor cells, while having a normal cell growth inhibitory activity, as refl ected by the inhibition of the DNA synthesis. It has been presently sh own that while at the clinically relevant concentrations some of these H(IC)-binding drugs mildly stimulated (up to 15%) the cell growth in the human lines studied when used as single agents, in most instances this stimulation did not exceed 10% above the control values. When use d in combination with ONC, neither of these H(IC)-binding drugs demons trated any apparent synergistic activity as judged from the ED50 value s. However, the combinations of DPPE+TFP and AMT+TFP, in both the ASPC -1 and COLO 320DM lines, demonstrated a significant cell growth inhibi tion, while there was no difference between the effects of AMT alone a nd the AMT+TFP combination in the U87MG line. The most effective cell growth inhibition was obtained when ONC was combined with DPPE+TFP and /or AMT+TFP, as reflected by the significantly decreased ED50 values.