Synergy of Taxol and radioimmunotherapy with yttrium-90-labeled chimeric L6 antibody: Efficacy and toxicity in breast cancer xenografts

Sally J. Denardo, David L. Kukis, Linda A. Kroger, Robert T O'Donnell, Kathleen R. Lamborn, Laird A. Miers, David G. Denardo, Claude F. Meares, Gerald L Denardo

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

Synergistic multimodality therapy is needed for breast cancer. Breast cancer frequently has p53 mutations that result in cells less likely to undergo apoptosis when exposed to DNA damaging therapies. Taxol (paclitaxel) is more effective in the presence of mutant p53. 90Y-labeled DOTA-peptide- ChL6 (90Y-ChL6, where ChL6 is chimeric L6 antibody and DOTA is 1,4,7,10- tetraazacyclododecane N,N',N'',N'''-tetraacetic acid) is a novel radioimmunoconjugate for targeting radiation to cancer. It has a stable metal chelator and a peptide linker that can be catabolized by hepatic lysozymes. This study was designed to assess potential synergism between Taxol and 90Y-ChL6 in a highly anaplastic breast cancer model, HBT 3477. There was no tumor response in mice receiving ChL6 or Taxol alone. In mice receiving 90Y-ChL6 alone, 79% (15 of 19) of tumors responded although none were cured. If Taxol was administered 24-72 hours before 90Y-ChL6, again, 79% (23 of 29) of tumors responded but 21% were cured. When Taxol was administered 6 or 24 hours after 90Y-ChL6, 100% (46 of 46) of tumors responded and 48% were cured. Taxol given with 90Y-ChL6 did not substantially increase toxicity. Enhancement of the therapeutic effect when Taxol was added to 90Y-ChL6 therapy for HBT 3477 xenografts was striking. The synergistic therapeutic effect of Taxol with 90Y-ChL6 may relate to the p53 mutant status and BCL2 expression in HBT 3477 cells, observations that increase the likelihood that the results of this study are relevant to therapy for breast cancer in patients. In conclusion, Taxol seemed to be synergistic with 90Y-ChL6 in this human breast cancer model. Up to 50% of these anaplastic breast cancer xenografts were cured by combined modality therapy.

Original languageEnglish (US)
Pages (from-to)4000-4004
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number8
DOIs
StatePublished - Apr 15 1997

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Radioimmunotherapy
Yttrium
Paclitaxel
Heterografts
Breast Neoplasms
Antibodies
Therapeutic Uses
Neoplasms
ChL6 monoclonal antibody
Immunoconjugates
Combined Modality Therapy
Peptides
Muramidase
Chelating Agents
Genetic Therapy

Keywords

  • antibody
  • breast carcinoma

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Synergy of Taxol and radioimmunotherapy with yttrium-90-labeled chimeric L6 antibody : Efficacy and toxicity in breast cancer xenografts. / Denardo, Sally J.; Kukis, David L.; Kroger, Linda A.; O'Donnell, Robert T; Lamborn, Kathleen R.; Miers, Laird A.; Denardo, David G.; Meares, Claude F.; Denardo, Gerald L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 94, No. 8, 15.04.1997, p. 4000-4004.

Research output: Contribution to journalArticle

Denardo, Sally J. ; Kukis, David L. ; Kroger, Linda A. ; O'Donnell, Robert T ; Lamborn, Kathleen R. ; Miers, Laird A. ; Denardo, David G. ; Meares, Claude F. ; Denardo, Gerald L. / Synergy of Taxol and radioimmunotherapy with yttrium-90-labeled chimeric L6 antibody : Efficacy and toxicity in breast cancer xenografts. In: Proceedings of the National Academy of Sciences of the United States of America. 1997 ; Vol. 94, No. 8. pp. 4000-4004.
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abstract = "Synergistic multimodality therapy is needed for breast cancer. Breast cancer frequently has p53 mutations that result in cells less likely to undergo apoptosis when exposed to DNA damaging therapies. Taxol (paclitaxel) is more effective in the presence of mutant p53. 90Y-labeled DOTA-peptide- ChL6 (90Y-ChL6, where ChL6 is chimeric L6 antibody and DOTA is 1,4,7,10- tetraazacyclododecane N,N',N'',N'''-tetraacetic acid) is a novel radioimmunoconjugate for targeting radiation to cancer. It has a stable metal chelator and a peptide linker that can be catabolized by hepatic lysozymes. This study was designed to assess potential synergism between Taxol and 90Y-ChL6 in a highly anaplastic breast cancer model, HBT 3477. There was no tumor response in mice receiving ChL6 or Taxol alone. In mice receiving 90Y-ChL6 alone, 79{\%} (15 of 19) of tumors responded although none were cured. If Taxol was administered 24-72 hours before 90Y-ChL6, again, 79{\%} (23 of 29) of tumors responded but 21{\%} were cured. When Taxol was administered 6 or 24 hours after 90Y-ChL6, 100{\%} (46 of 46) of tumors responded and 48{\%} were cured. Taxol given with 90Y-ChL6 did not substantially increase toxicity. Enhancement of the therapeutic effect when Taxol was added to 90Y-ChL6 therapy for HBT 3477 xenografts was striking. The synergistic therapeutic effect of Taxol with 90Y-ChL6 may relate to the p53 mutant status and BCL2 expression in HBT 3477 cells, observations that increase the likelihood that the results of this study are relevant to therapy for breast cancer in patients. In conclusion, Taxol seemed to be synergistic with 90Y-ChL6 in this human breast cancer model. Up to 50{\%} of these anaplastic breast cancer xenografts were cured by combined modality therapy.",
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AU - O'Donnell, Robert T

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AU - Miers, Laird A.

AU - Denardo, David G.

AU - Meares, Claude F.

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