Document Detail


Doxorubicin conjugated with a monoclonal antibody directed to a human melanoma-associated proteoglycan suppresses the growth of established tumor xenografts in nude mice.
MedLine Citation:
PMID:  3422487     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
H M Yang; R A Reisfeld
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  85     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  1988 Feb 
Date Detail:
Created Date:  1988-03-21     Completed Date:  1988-03-21     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1189-93     Citation Subset:  IM    
Affiliation:
Department of Immunology, Scripps Clinic and Research Foundation, La Jolla, CA 92037.
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MeSH Terms
Descriptor/Qualifier:
Adenocarcinoma / drug therapy
Animals
Antibodies, Monoclonal / administration & dosage*
Antibodies, Neoplasm / administration & dosage*
Doxorubicin / administration & dosage*,  pharmacokinetics,  therapeutic use
Female
Humans
Lung Neoplasms / drug therapy
Melanoma / immunology*
Melanoma, Experimental / drug therapy*,  ultrastructure
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Transplantation
Proteochondroitin Sulfates / immunology*
Proteoglycans / immunology*
Tissue Distribution
Transplantation, Heterologous
Grant Support
ID/Acronym/Agency:
CA 42508/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antibodies, Neoplasm; 0/Proteochondroitin Sulfates; 0/Proteoglycans; 23214-92-8/Doxorubicin
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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