This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 Wang, S.-M. Articles by Roffler, S. R. Search for Related Content PubMed PubMed Citation Articles by Wang, S.-M. Articles by Roffler, S. R.

Specific Activation of Glucuronide Prodrugs by Antibody-targeted Enzyme Conjugates for Cancer Therapy¹

Institute of Biomedical Sciences, Academia Sinica, Taipei 11529 [S-M. W., J. C. N., E. T., S. R. R.], and Institute of Pharmacy and Medical Laboratories [J-W. C.] and Department of Microbiology and Immunology [M-Y. Y.], National Defense Medical Center, Taipei 10764, Taiwan, Republic of China

Cancer chemotherapy may be improved by increasing antineoplastic drug specificity for tumor cells. We have synthesized a glucuronide prodrug that can be enzymatically converted to an antineoplastic agent at tumor cells that are able to bind ß-glucuronidase-monoclonal antibody conjugates. The glucuronide prodrug BHAMG, the tetra-n-butyl ammonium salt of (p-di-2-chloroethylaminophenyl-ß-D-glucopyranosid) uronic acid, was 150 times less toxic than the parent drug, N,N-di-(2-chloroethyl)-4-hydroxyaniline, to HepG2 human hepatoma cells and over 1000-fold less toxic than the parent drug to AS-30D rat hepatoma cells in vitro. In the presence of ß-glucuronidase, BHAMG was activated and became as toxic as the parent drug N,N-di-(2-chloroethyl)4-hydroxyaniline. A conjugate (RH1-ßG) was formed by linking ß-glucuronidase to a monoclonal antibody which binds to an antigen expressed on the surface of AS-30D cells. The concentration of BHAMG causing 50% inhibition of AS-30D cellular protein synthesis was reduced over 1000-fold, from >770 µM to <0.74 µM after these cells were preincubated with RH1-ßG. Specificity of BHAMG activation at antigen-positive cells was shown by monoclonal antibody RH1 blocking of RH1-ßG conversion of BHAMG to toxic drug and by the inability of BHAMG to be converted to active drug when antigen-negative control cells were preincubated with RH1-ßG. Our results show that the targeted-ß-glucuronidase activation of BHAMG can increase the specificity of chemotherapy for rat hepatoma in vitro and suggest that the targeted activation of glucuronide prodrugs may be useful for cancer therapy.

¹ Supported by grants and allocations from the National Science Council and Academia Sinica, Taipei, Taiwan, Republic of China.

² Present Address: Division of Colon and Rectal Surgery, Tri-Service General Hospital, Taipei, Taiwan, Republic of China.

³ To whom requests for reprints should be addressed.

Received 2/27/92. Accepted 6/ 5/92.

This article has been cited by other articles:

				M. Michael and M.M. Doherty Tumoral Drug Metabolism: Overview and Its Implications for Cancer Therapy J. Clin. Oncol., January 1, 2005; 23(1): 205 - 229. [Abstract] [Full Text] [PDF]

				G. K. Smith, S. Banks, T. A. Blumenkopf, M. Cory, J. Humphreys, R. M. Laethem, J. Miller, C. P. Moxham, R. Mullin, P. H. Ray, et al. Toward Antibody-directed Enzyme Prodrug Therapy with the T268G Mutant of Human Carboxypeptidase A1 and Novel in Vivo Stable Prodrugs of Methotrexate J. Biol. Chem., June 20, 1997; 272(25): 15804 - 15816. [Abstract] [Full Text] [PDF]