During the past year, we have made strides in understanding in vitro and in vivo effects of Merck L651582, now called CAI for carboxyamido-imidazole [NSC 609974D]. In collaboration with Dr. Chris Felder of the NIMH, we have demonstrated that CAI inhibits receptor-gated calcium influx and arachidonic acid metabolism in muscarinic receptor-transfected CHO cells. This inhibition was dose dependent and was within the concentration range that we have shown previously to inhibit AMF-stimulated inositol phosphate production. We have initiated studies to identify potential CAI effects against other components of the metastatic cascade and have shown that CAI inhibits type IV collagenase production and coordinately, TIMP-2 production. Animal studies have yielded new results on efficacy and preclinical pharmacology. We have demonstrated inhibition of OVCAR-3 tumor progression and metastasis and inhibition of A2058 human melanoma tumor incidence and growth in experimental animals, both with orally delivered CAI. Oral administration results in plasma levels in mice, rats, and dogs that are within the range of concentrations which in vitro inhibit signal transduction, growth, and motility [1-5 (mu)g/ml]. CAI has passed into phase IIb preclinical development and is presently undergoing INDA-directed toxicity studies with intent to initiate Phase I clinical trials within the calendar year 1991. In addition, the patent application submitted in 1989 has had claims approved for use as an anticancer agent for ovarian cancer; further claims remain under review.
