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 ASPC-1 pancreatic and A-549 lung carcinoma cells, respectively. It has recently been reported that several drugs known to bind to the intracellular antiestrogen binding site (AEBS)/histamine (H(IC)) receptors, including tricyclic (amitriptyline, AMT) and non-tricyclic (fluoxetine, FLX) antidepressants, TMX, phenothiazines and the prototype H(IC)-binder DPPE, can stimulate the in vitro and in vivo growth of rodent tumor cells, while having a normal cell growth inhibitory activity, as reflected by the inhibition of the DNA synthesis. It has been presently shown 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 used in combination with ONC, neither of these H(IC)-binding drugs demonstrated any apparent synergistic activity as judged from the ED50 values. However, the combinations of DPPE+TFP and AMT+TFP, in both the ASPC-1 and COLO 320DM lines, demonstrated a significant cell growth inhibition, while there was no difference between the effects of AMT alone and 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.

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