Inhibition of tumour growth by marimastat in a human xenograft model of gastric cancer: relationship with levels of circulating CEA

Inhibition of matrix metalloproteinases (MMPs) is an attractive approach to adjuvant therapy in the treatment of cancer. Marimastat is the first orall y administered, synthetic MMP inhibitor to be evaluated, in this capacity, in the clinic. Measurement of the rate of change of circulating tumour anti gens was used for evaluating biological activity and defining optimum dosag e in the early clinical trials of marimastat, Although tumour antigen level s have been used in the clinical management of cancer for many years, they have not been validated as markers of disease progression. In order to inve stigate the relationship between the effects of marimastat on tumour growth and circulating tumour antigen levels, mice bearing the human gastric tumo ur, MGLVA1, were treated with marimastat. The MMP inhibitor exerted a signi ficant therapeutic effect, reducing tumour growth rate by 48% (P = 0.0005), and increasing median survival from 19 to 30 days (P = 0.0001). In additio n, carcinoembryonic antigen (CEA) levels were measured in serum samples fro m animals sacrificed at regular intervals, and correlated with excised tumo ur weight. It was shown that the natural log of the CEA concentration was l inearly related to the natural log of the tumour weight and that treatment was not a significant factor in this relationship (P = 0.7). In conclusion, circulating CEA levels were not directly affected by marimastat, but did r eflect tumour size. these results support the use of cancer antigens as mar kers of biological activity in early phase trials of non-cytotoxic anticanc er agents.