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Doxorubicin conjugated with a monoclonal-antibody directed to a human melanoma-associated proteoglycan suppresses the growth of established tumor xenografts in nude-mice

Academic Article
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Overview

authors

  • Yang, H. M.
  • Reisfeld, Ralph

publication date

  • 1988

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Doxorubicin (DXR) was covalently conjugated to a monoclonal antibody (mAb), 9.2.27 (IgG2a), which recognizes a chondroitin sulfate proteoglycan expressed preferentially on the surface of human melanoma cells. Immunoconjugates with a molar ratio of DXR to mAb ranging from 2:1 to 10:1 were obtained by coupling the drug via an acid-sensitive linker, cis-aconitic anhydride. The immunoreactivity of mAb 9.2.27 was well retained after conjugation. DXR-mAb 9.2.27 conjugates were found to be 2 orders of magnitude more potent in killing tumor cells in vitro (IC50 = 0.1 microM) than free drug targeted to drug receptor(s). Most significantly, DXR-mAb 9.2.27 immunoconjugates specifically suppressed the growth of established tumors in vivo and prolonged the life-span of tumor-bearing nude mice. This suppression of melanoma growth achieved by the immunoconjugate was both tumor and antibody specific. A biodistribution study indicated that DXR-mAb 9.2.27 conjugates delivered at least 4 times more DXR (3.7% total injected dose per g of tumor) as compared to free DXR alone (0.8% total injected dose per g of tumor) in tumor-bearing nude mice 48 hr postinjection. The tumor-suppressive effects of DXR-mAb 9.2.27 conjugates are even more remarkable since free DXR did not suppress tumor growth in vivo and also because this drug per se is known to be quite ineffective for the treatment of human melanoma.

subject areas

  • Adenocarcinoma
  • Animals
  • Antibodies, Monoclonal
  • Antibodies, Neoplasm
  • Chondroitin Sulfate Proteoglycans
  • Doxorubicin
  • Female
  • Humans
  • Lung Neoplasms
  • Melanoma
  • Melanoma, Experimental
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Transplantation
  • Proteoglycans
  • Tissue Distribution
  • Transplantation, Heterologous
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Identity

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.85.4.1189

PubMed ID

  • 3422487
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Additional Document Info

start page

  • 1189

end page

  • 1193

volume

  • 85

issue

  • 4

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