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. 1989 May;86(10):3778–3781. doi: 10.1073/pnas.86.10.3778

Inhibition of human tumor growth in nude mice by a conjugate of doxorubicin with monoclonal antibodies to epidermal growth factor receptor.

E Aboud-Pirak 1, E Hurwitz 1, F Bellot 1, J Schlessinger 1, M Sela 1
PMCID: PMC287223  PMID: 2786202

Abstract

Monoclonal antibodies that recognize the extracellular domain of the epidermal growth factor receptor (mAb108) were conjugated with doxorubicin through a dextran bridge. Several antibody-drug conjugates, containing different amounts of doxorubicin, retained binding capacity to human epidermoid carcinoma (KB) cells overexpressing epidermal growth factor receptors. Slight decrease in drug cytotoxicity was seen in in vitro tests, as determined either by inhibition of thymidine incorporation into cells or by reduction in number and size of KB-cell colonies. Yet, when tested in vivo against KB tumor xenografted into nude mice, the anti-epidermal growth factor-receptor drug conjugates with high drug-substitution levels were significantly more effective than free doxorubicin, antibody alone, mixture of dextran-doxorubicin and antibody, or drug conjugated with irrelevant antibody. When the labile covalent bonds linking antibody to dextran bridge were stabilized by reduction, the therapeutic efficacy of the conjugate was markedly decreased. These results show that antibodies against the extracellular domain of the epidermal growth factor can deliver doxorubicin specifically and efficiently to tumor sites that express high receptor levels exerting a specific antitumor effect.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aboud-Pirak E., Hurwitz E., Pirak M. E., Bellot F., Schlessinger J., Sela M. Efficacy of antibodies to epidermal growth factor receptor against KB carcinoma in vitro and in nude mice. J Natl Cancer Inst. 1988 Dec 21;80(20):1605–1611. doi: 10.1093/jnci/80.20.1605. [DOI] [PubMed] [Google Scholar]
  2. Dillman R. O., Shawler D. L., Johnson D. E., Meyer D. L., Koziol J. A., Frincke J. M. Preclinical trials with combinations and conjugates of T101 monoclonal antibody and doxorubicin. Cancer Res. 1986 Oct;46(10):4886–4891. [PubMed] [Google Scholar]
  3. Gullick W. J., Marsden J. J., Whittle N., Ward B., Bobrow L., Waterfield M. D. Expression of epidermal growth factor receptors on human cervical, ovarian, and vulval carcinomas. Cancer Res. 1986 Jan;46(1):285–292. [PubMed] [Google Scholar]
  4. HUNTER W. M., GREENWOOD F. C. Preparation of iodine-131 labelled human growth hormone of high specific activity. Nature. 1962 May 5;194:495–496. doi: 10.1038/194495a0. [DOI] [PubMed] [Google Scholar]
  5. Hurwitz E., Levy R., Maron R., Wilchek M., Arnon R., Sela M. The covalent binding of daunomycin and adriamycin to antibodies, with retention of both drug and antibody activities. Cancer Res. 1975 May;35(5):1175–1181. [PubMed] [Google Scholar]
  6. Hurwitz E., Maron R., Bernstein A., Wilchek M., Sela M., Arnon R. The effect in vivo of chemotherapeutic drug--antibody conjugates in two murine experimental tumor systems. Int J Cancer. 1978 Jun 15;21(6):747–755. doi: 10.1002/ijc.2910210612. [DOI] [PubMed] [Google Scholar]
  7. Libermann T. A., Razon N., Bartal A. D., Yarden Y., Schlessinger J., Soreq H. Expression of epidermal growth factor receptors in human brain tumors. Cancer Res. 1984 Feb;44(2):753–760. [PubMed] [Google Scholar]
  8. Lyall R. M., Hwang J. L., Cardarelli C., FitzGerald D., Akiyama S., Gottesman M. M., Pastan I. Isolation of human KB cell lines resistant to epidermal growth factor-Pseudomonas exotoxin conjugates. Cancer Res. 1987 Jun 1;47(11):2961–2966. [PubMed] [Google Scholar]
  9. Ozawa S., Ueda M., Ando N., Abe O., Shimizu N. High incidence of EGF receptor hyperproduction in esophageal squamous-cell carcinomas. Int J Cancer. 1987 Mar 15;39(3):333–337. doi: 10.1002/ijc.2910390311. [DOI] [PubMed] [Google Scholar]
  10. Ro J., North S. M., Gallick G. E., Hortobagyi G. N., Gutterman J. U., Blick M. Amplified and overexpressed epidermal growth factor receptor gene in uncultured primary human breast carcinoma. Cancer Res. 1988 Jan 1;48(1):161–164. [PubMed] [Google Scholar]
  11. Schlessinger J. Allosteric regulation of the epidermal growth factor receptor kinase. J Cell Biol. 1986 Dec;103(6 Pt 1):2067–2072. doi: 10.1083/jcb.103.6.2067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Tsukada Y., Bischof W. K., Hibi N., Hirai H., Hurwitz E., Sela M. Effect of a conjugate of daunomycin and antibodies to rat alpha-fetoprotein on the growth of alpha-fetoprotein-producing tumor cells. Proc Natl Acad Sci U S A. 1982 Jan;79(2):621–625. doi: 10.1073/pnas.79.2.621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Tsukada Y., Ohkawa K., Hibi N. Therapeutic effect of treatment with polyclonal or monoclonal antibodies to alpha-fetoprotein that have been conjugated to daunomycin via a dextran bridge: studies with an alpha-fetoprotein-producing rat hepatoma tumor model. Cancer Res. 1987 Aug 15;47(16):4293–4295. [PubMed] [Google Scholar]
  14. Yamamoto T., Kamata N., Kawano H., Shimizu S., Kuroki T., Toyoshima K., Rikimaru K., Nomura N., Ishizaki R., Pastan I. High incidence of amplification of the epidermal growth factor receptor gene in human squamous carcinoma cell lines. Cancer Res. 1986 Jan;46(1):414–416. [PubMed] [Google Scholar]
  15. Yang H. M., Reisfeld R. A. Doxorubicin conjugated with a monoclonal antibody directed to a human melanoma-associated proteoglycan suppresses the growth of established tumor xenografts in nude mice. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1189–1193. doi: 10.1073/pnas.85.4.1189. [DOI] [PMC free article] [PubMed] [Google Scholar]

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