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Comparison of two anthracycline-based prodrugs for activation by a monoclonal antibody-β-glucuronidase conjugate in the specific treatment of cancer

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Abstract

Antibody-directed enzyme prodrug therapy (ADEPT) may improve the therapeutic index of cytostatic agents. We compared two prodrugs, epirubicin-glucuronide (Epi-glu) and doxorubicin-spacer-glucuronide (Dox-sp-glu), for their cytotoxicity on activation by a monoclonal antibody-enzyme conjugate bound to tumor cells. The results showed that the prodrugs were 10 (Dox-sp-glu) and 100 (Epi-glu) times less toxic than the parent drugs against OVCAR-3 cells. This difference was a result of the hydrophilic property of the prodrugs resulting in a reduced cellular uptake. The enzyme-catalyzed hydrolysis of Dox-sp-glu byE. coli-derived β-glucuronidase (GUS) (K m 500 μM,V max 21,000 μmol/min/g) was much more efficient than that of Epi-glu (K m 10 μM,V max 40 μmol/min/g). Incubation of OVCAR-3 cells with an enzyme-immunoconjugate prepared from monoclonal antibody 323/A3 andE. coli-derived GUS before treatment with prodrugs completely restored the cytotoxicity of the prodrugs to the level of the parent drugs.

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References

  1. Haisma, H. J., Boven, E., van Muijen, M., de Jong, J., van der Vijgh, W. J. F., and Pinedo, H. M. (1992)Br. J. Cancer 66, 474–478.

    PubMed  CAS  Google Scholar 

  2. Edwards, D. P., Grzyb, K. T., Dressler, L. G., Mansel, R. E., Zara, D. T., Sledge, G. W., et al. (1986)Cancer Res. 46, 1306–1311.

    PubMed  CAS  Google Scholar 

  3. Andrianomenjanahary, S., Dong, X., Florent, J. C., Gaudel, G., Gesson, J. P., Jacquesy, J. C. et al. (1992)Bioorg. Med. Chem. Letts. 2, 1093–1096.

    Article  CAS  Google Scholar 

  4. Eksborg, S., Ehrsson, H., and Ekqvist, B. (1982)Cancer Chemother. Pharmacol. 10, 7–10.

    Article  PubMed  CAS  Google Scholar 

  5. Hamilton, T. C., Young, R. C., Louie, K. G., Behrens, B. C., Mckoy, W. M., Grotzinger, K. R., et al. (1984)Cancer Res. 44, 5286–5290.

    PubMed  CAS  Google Scholar 

  6. Bagshawe, K. D., Sharma, S. K., Springer, C. J., Antoniw, P., Boden, J. A., Rogers, G. T., et al. (1991)Disease Markers 9, 233–238.

    PubMed  CAS  Google Scholar 

  7. Bosslet, K., Czech, J., Lorenz, P., Sedlacek, H. H., Schuemann, M., and Seman, G. (1992)Br. J. Cancer 65, 234–238.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Medical Oncology, Free University Hospital, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

    H. J. Haisma, M. van Muijen, H. M. Pinedo & E. Boven

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  1. H. J. Haisma
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  2. M. van Muijen
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  3. H. M. Pinedo
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  4. E. Boven
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Haisma, H.J., van Muijen, M., Pinedo, H.M. et al. Comparison of two anthracycline-based prodrugs for activation by a monoclonal antibody-β-glucuronidase conjugate in the specific treatment of cancer. Cell Biophysics 24, 185–192 (1994). https://doi.org/10.1007/BF02789229

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  • DOI: https://doi.org/10.1007/BF02789229

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