This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yazdi, P. T. Articles by Murphy, R. M. Search for Related Content PubMed PubMed Citation Articles by Yazdi, P. T. Articles by Murphy, R. M.

Influence of Cellular Trafficking on Protein Synthesis Inhibition of Immunotoxins Directed against the Transferrin Receptor¹

Department of Chemical Engineering, University of Wisconsin, Madison, Wisconsin 53706

Previously, a quantitative analysis that related protein synthesis inhibition of transferrin-toxin conjugates to the cellular trafficking of transferrin was proposed (P. T. Yazdi and R. M. Murphy, Cancer Res., 54: 6387–6394, 1994). Here, this work is extended to evaluate cellular trafficking of anti-transferrin receptor antibodies and protein synthesis inhibition kinetics of immunotoxins constructed from the same antibodies and the toxin gelonin. Cellular trafficking models for two monoclonal anti-transferrin receptor antibodies (5E9 and OKT9) in HeLa cells were developed. The two mAbs had similar trafficking parameters, which differed significantly from those for transferrin. Protein synthesis inhibition kinetics for immunotoxins constructed from 5E9 or OKT9 and gelonin were measured. Analysis of the data using our previously proposed relationship between protein synthesis and cellular trafficking indicated that the relationship is also valid for these new systems. The protein synthesis inhibition constans for 5E9-gelonin and OKT9-gelonin conjugates were similar to those for the transferrin-gelonin conjugate. These results suggest that it may be possible to predict the efficacy of gelonin immunotoxins from knowledge of the trafficking of the corresponding targeting agent. A sensitivity analysis showed which cellular trafficking parameters have the greatest influence on immunotoxin efficacy and are, therefore, the most likely to be profitably manipulated.

¹ This work was supported by National Science Foundation Presidential Young Investigator Award BCS-9057661.

² To whom requests for reprints should be addressed, at University of Wisconsin, 1415 Johnson Drive, Madison, WI 53706.

Received 2/22/95. Accepted 7/ 6/95.

This article has been cited by other articles:

				R. A. Dumont, I. Hildebrandt, H. Su, R. Haubner, G. Reischl, J. G. Czernin, P. S. Mischel, and W. A. Weber Noninvasive Imaging of {alpha}V{beta}3 Function as a Predictor of the Antimigratory and Antiproliferative Effects of Dasatinib Cancer Res., April 1, 2009; 69(7): 3173 - 3179. [Abstract] [Full Text] [PDF]

				D. W. Bartlett, H. Su, I. J. Hildebrandt, W. A. Weber, and M. E. Davis Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging PNAS, September 25, 2007; 104(39): 15549 - 15554. [Abstract] [Full Text] [PDF]

				S. F. Atkinson, T. Bettinger, L. W. Seymour, J.-P. Behr, and C. M. Ward Conjugation of Folate via Gelonin Carbohydrate Residues Retains Ribosomal-inactivating Properties of the Toxin and Permits Targeting to Folate Receptor Positive Cells J. Biol. Chem., July 20, 2001; 276(30): 27930 - 27935. [Abstract] [Full Text] [PDF]