PRECLINICAL PHARMACOLOGY OF CHOLERA-TOXIN

Cholera toxin was selected for pharmacologic evaluation by the Nationa l Caner Institute on the basis of antiproliferative activity against s mall-cell and nonsmall-cell lung-cancer cell lines. A feature common t o the sensitive cell lines was abundant expression of G(M1) gangliosid e, the cellular receptor for cholera toxin. A sandwich enzyme-linked i mmunosorbent assay (ELISA) was developed to quantitate cholera toxin i n biological fluids. A sigmoidal relationship was observed between the cholera toxin plasma concentration and the absorbance at 490 nm (OD49 0) of the product of horseradish peroxidase-catalyzed oxidation of o-p henylenediamine over the range of 6.25-1,600 ng/ml. Legit transformati on of the OD490 data was linear over the entire concentration range an d assay variability was less than 25%. Cholera toxin was stable in mur ine and human whole blood and plasma. Following i.v. administration of 1,500 mu g/kg to male CD2F(1) mice, cholera toxin plasma elimination was described by a two-compartment open model. The half-lives (t(1/2)a lpha, t(1/2)beta), plasma clearance, and steady-state volume of distri bution were 0.7 min, 49 min, 24 ml min(-1) kg(-1) 912 ml/kg, respectiv ely. Cholera toxin was not detected in plasma following an s.c. dose o f 1,500 mu g/kg. Urinary recovery following intravenous drug administr ation was less than 0.1%.