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Kinetic Analysis of Choriocarcinoma Cell Intoxication Induced by Ricin and Ricin A Chain Immunotoxin¹

Laboratoire d' Immunobiologie des Tumeurs, U.A. 1156 C.N.R.S. [K. B., T. T., M. L.], and Laboratoire de Pharmacologie Moléculaire, L.A.147 C.N.R.S. and U.140 I.N.S.E.R.M. [S. J., J-B. L. P.], Institute Gustave Roussy, 94805 Villejuif, Cedex, France

The kinetics of protein synthesis inhibition was studied in the choriocarcinoma-derived BeWo cell line treated with ricin and an immunotoxin (IT) constructed by linking a specific antibody to the A chain of ricin. The IT was specifically cytotoxic to BeWo and other choriocarcinoma cells. The multistep process underlying this kinetics was explored using two mathematical models where the protein synthesis-inactivation step is preceded by one or two processing rate-limiting steps. Theoretical curves were computed for different concentrations of toxic reagents. Two processing steps were found necessary to predict the duration of the observed latent period before initiation of protein synthesis inhibition. With this model, a satisfactory fit was obtained. A mathematical modeling of the intoxication induced by ricin or ricin A chain IT thus requires two processing steps to account for the data observed. In addition, the data suggest that the cytoplasmic internalization of ricin is a slow process compensated by an extremely fast enzymatic inactivation of ribosomal activity. This implies that in this and similar systems, endocytosis might not be involved in the cytoplasmic internalization of the few molecules of ricin A chain responsible for cell intoxication.

¹ This work was supported in part by grants from I.N.S.E.R.M. (76768I.), A.R.C., F.R.M., and Université P. et M. Curie, Paris VI.

² To whom requests for reprints should be addressed.

Received 8/18/87. Accepted 11/ 3/87.