Preclinical pharmacology of cholera toxin.
Cholera toxin was selected for pharmacologic evaluation by the National Cancer Institute on the basis of antiproliferative activity against small-cell and non-small-cell lung-cancer cell lines. A feature common to the sensitive cell lines was abundant expression of GM1 ganglioside, the cellular receptor for cholera toxin. A sandwich enzyme-linked immunosorbent assay (ELISA) was developed to quantitate cholera toxin in biological fluids. A sigmoidal relationship was observed between the cholera toxin plasma concentration and the absorbance at 490 nm (OD490) of the product of horseradish peroxidase-catalyzed oxidation of o-phenylenediamine over the range of 6.25-1,600 ng/ml. Logit transformation of the OD490 data was linear over the entire concentration range and assay variability was less than 25%. Cholera toxin was stable in murine and human whole blood and plasma. Following i.v. administration of 1,500 micrograms/kg to male CD2F1 mice, cholera toxin plasma elimination was described by a two-compartment open model. The half-lives (t1/2 alpha, t1/2 beta), plasma clearance, and steady-state volume of distribution were 0.7 min, 49 min, 24 ml min-1 kg-1 912 ml/kg, respectively. Cholera toxin was not detected in plasma following an s.c. dose of 1,500 micrograms/kg. Urinary recovery following intravenous drug administration was less than 0.1%.
Reid
J M
JM
Department of Oncology, Research, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
Benson
J W
JW
Viallet
J
J
Ames
M M
MM
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung; D018288:Carcinoma, Small Cell; D002460:Cell Line; D002772:Cholera Toxin / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*; D004355:Drug Stability; D004797:Enzyme-Linked Immunosorbent Assay; D006735:Horseradish Peroxidase; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008175:Lung Neoplasms; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008954:Models, Biological; D010084:Oxidation-Reduction; D010655:Phenylenediamines; D014407:Tumor Cells, Cultured
D010655:Phenylenediamines; C034193:1,2-diaminobenzene; D002772:Cholera Toxin; D006735:Horseradish Peroxidase