Effect of Antigenic Heterogeneity on the Efficacy of Enhanced Delivery of Antibody-targeted Chemotherapy in A Human Lung Cancer Intracerebral Xenograft Model in Rats

Edward Neuwelt, Lori A. Thrun, Shannan Walker-Rosenfeld, Andrew T. Cave, Leslie Muldoon, Arun P. Amar, Roberta P. Glick, Terry Lichtor

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

OBJECTIVE: The SGN-15 monoclonal antibody-doxorubicin immunoconjugate is toxic to LewisY antigen-expressing cells and is effective against intracerebral tumors in nude rats when delivery is enhanced with osmotic disruption of the blood-brain barrier (BBB). We tested whether doxorubicin released locally in antigen-expressing cells would affect adjacent non-antigen-expressing cells in heterogeneously expressing intracerebral tumors. METHODS: Nude rats with intracerebral xenografts of human small cell lung carcinoma cells with high (n = 10) or low (n = 23) LewisY antigen expression were treated with SGN-15 at a low (10 mg/kg) or high (140 mg/kg) antibody dose, administered intra-arterially with BBB disruption, and tumor volumes and antigen expression were evaluated after 6 days. RESULTS: BBB disruption-enhanced delivery of SGN-15 (10 mg/kg) reduced the high-expressor tumor volume from 26.1 ± 3.7 mm3 (n = 7) in untreated control animals to 6.7 ± 4.6 mm3 (n = 3, P <0.05). Untreated high-expressor tumors exhibited uniform prominent LewisY antigen staining (97.6 ± 0.9% positive, n = 4), whereas treated tumors demonstrated areas of nil, moderate, and prominent staining (71.0 ± 8.5% positive, n = 3, P <0.05). In intracerebral tumors with low initial antigen expression, BBB disruption-enhanced delivery of a low dose of immunoconjugate was significantly effective, but treated tumors demonstrated low levels of antigen expression. An increase in the immunoconjugate dose did not significantly alter either efficacy or antigen expression. CONCLUSION: Immunoconjugate delivered across the BBB was effective against antigen-positive tumor cells, but there was not an effective chemical bystander effect against antigen-negative tumor cells.

Original languageEnglish (US)
Pages (from-to)1406-1413
Number of pages8
JournalNeurosurgery
Volume53
Issue number6
StatePublished - Dec 2003

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Heterografts
Lung Neoplasms
Immunoconjugates
Blood-Brain Barrier
Antigens
Drug Therapy
Antibodies
Neoplasm Antigens
Nude Rats
Neoplasms
Tumor Burden
Doxorubicin
Staining and Labeling
Bystander Effect
Poisons
Small Cell Lung Carcinoma
Monoclonal Antibodies

Keywords

  • Blood-brain barrier
  • Brain tumor
  • Doxorubicin
  • Immunoconjugate

ASJC Scopus subject areas

  • Clinical Neurology
  • Surgery

Cite this

Effect of Antigenic Heterogeneity on the Efficacy of Enhanced Delivery of Antibody-targeted Chemotherapy in A Human Lung Cancer Intracerebral Xenograft Model in Rats. / Neuwelt, Edward; Thrun, Lori A.; Walker-Rosenfeld, Shannan; Cave, Andrew T.; Muldoon, Leslie; Amar, Arun P.; Glick, Roberta P.; Lichtor, Terry.

In: Neurosurgery, Vol. 53, No. 6, 12.2003, p. 1406-1413.

Research output: Contribution to journalArticle

Neuwelt, Edward ; Thrun, Lori A. ; Walker-Rosenfeld, Shannan ; Cave, Andrew T. ; Muldoon, Leslie ; Amar, Arun P. ; Glick, Roberta P. ; Lichtor, Terry. / Effect of Antigenic Heterogeneity on the Efficacy of Enhanced Delivery of Antibody-targeted Chemotherapy in A Human Lung Cancer Intracerebral Xenograft Model in Rats. In: Neurosurgery. 2003 ; Vol. 53, No. 6. pp. 1406-1413.
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abstract = "OBJECTIVE: The SGN-15 monoclonal antibody-doxorubicin immunoconjugate is toxic to LewisY antigen-expressing cells and is effective against intracerebral tumors in nude rats when delivery is enhanced with osmotic disruption of the blood-brain barrier (BBB). We tested whether doxorubicin released locally in antigen-expressing cells would affect adjacent non-antigen-expressing cells in heterogeneously expressing intracerebral tumors. METHODS: Nude rats with intracerebral xenografts of human small cell lung carcinoma cells with high (n = 10) or low (n = 23) LewisY antigen expression were treated with SGN-15 at a low (10 mg/kg) or high (140 mg/kg) antibody dose, administered intra-arterially with BBB disruption, and tumor volumes and antigen expression were evaluated after 6 days. RESULTS: BBB disruption-enhanced delivery of SGN-15 (10 mg/kg) reduced the high-expressor tumor volume from 26.1 ± 3.7 mm3 (n = 7) in untreated control animals to 6.7 ± 4.6 mm3 (n = 3, P <0.05). Untreated high-expressor tumors exhibited uniform prominent LewisY antigen staining (97.6 ± 0.9{\%} positive, n = 4), whereas treated tumors demonstrated areas of nil, moderate, and prominent staining (71.0 ± 8.5{\%} positive, n = 3, P <0.05). In intracerebral tumors with low initial antigen expression, BBB disruption-enhanced delivery of a low dose of immunoconjugate was significantly effective, but treated tumors demonstrated low levels of antigen expression. An increase in the immunoconjugate dose did not significantly alter either efficacy or antigen expression. CONCLUSION: Immunoconjugate delivered across the BBB was effective against antigen-positive tumor cells, but there was not an effective chemical bystander effect against antigen-negative tumor cells.",
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T1 - Effect of Antigenic Heterogeneity on the Efficacy of Enhanced Delivery of Antibody-targeted Chemotherapy in A Human Lung Cancer Intracerebral Xenograft Model in Rats

AU - Neuwelt, Edward

AU - Thrun, Lori A.

AU - Walker-Rosenfeld, Shannan

AU - Cave, Andrew T.

AU - Muldoon, Leslie

AU - Amar, Arun P.

AU - Glick, Roberta P.

AU - Lichtor, Terry

PY - 2003/12

Y1 - 2003/12

N2 - OBJECTIVE: The SGN-15 monoclonal antibody-doxorubicin immunoconjugate is toxic to LewisY antigen-expressing cells and is effective against intracerebral tumors in nude rats when delivery is enhanced with osmotic disruption of the blood-brain barrier (BBB). We tested whether doxorubicin released locally in antigen-expressing cells would affect adjacent non-antigen-expressing cells in heterogeneously expressing intracerebral tumors. METHODS: Nude rats with intracerebral xenografts of human small cell lung carcinoma cells with high (n = 10) or low (n = 23) LewisY antigen expression were treated with SGN-15 at a low (10 mg/kg) or high (140 mg/kg) antibody dose, administered intra-arterially with BBB disruption, and tumor volumes and antigen expression were evaluated after 6 days. RESULTS: BBB disruption-enhanced delivery of SGN-15 (10 mg/kg) reduced the high-expressor tumor volume from 26.1 ± 3.7 mm3 (n = 7) in untreated control animals to 6.7 ± 4.6 mm3 (n = 3, P <0.05). Untreated high-expressor tumors exhibited uniform prominent LewisY antigen staining (97.6 ± 0.9% positive, n = 4), whereas treated tumors demonstrated areas of nil, moderate, and prominent staining (71.0 ± 8.5% positive, n = 3, P <0.05). In intracerebral tumors with low initial antigen expression, BBB disruption-enhanced delivery of a low dose of immunoconjugate was significantly effective, but treated tumors demonstrated low levels of antigen expression. An increase in the immunoconjugate dose did not significantly alter either efficacy or antigen expression. CONCLUSION: Immunoconjugate delivered across the BBB was effective against antigen-positive tumor cells, but there was not an effective chemical bystander effect against antigen-negative tumor cells.

AB - OBJECTIVE: The SGN-15 monoclonal antibody-doxorubicin immunoconjugate is toxic to LewisY antigen-expressing cells and is effective against intracerebral tumors in nude rats when delivery is enhanced with osmotic disruption of the blood-brain barrier (BBB). We tested whether doxorubicin released locally in antigen-expressing cells would affect adjacent non-antigen-expressing cells in heterogeneously expressing intracerebral tumors. METHODS: Nude rats with intracerebral xenografts of human small cell lung carcinoma cells with high (n = 10) or low (n = 23) LewisY antigen expression were treated with SGN-15 at a low (10 mg/kg) or high (140 mg/kg) antibody dose, administered intra-arterially with BBB disruption, and tumor volumes and antigen expression were evaluated after 6 days. RESULTS: BBB disruption-enhanced delivery of SGN-15 (10 mg/kg) reduced the high-expressor tumor volume from 26.1 ± 3.7 mm3 (n = 7) in untreated control animals to 6.7 ± 4.6 mm3 (n = 3, P <0.05). Untreated high-expressor tumors exhibited uniform prominent LewisY antigen staining (97.6 ± 0.9% positive, n = 4), whereas treated tumors demonstrated areas of nil, moderate, and prominent staining (71.0 ± 8.5% positive, n = 3, P <0.05). In intracerebral tumors with low initial antigen expression, BBB disruption-enhanced delivery of a low dose of immunoconjugate was significantly effective, but treated tumors demonstrated low levels of antigen expression. An increase in the immunoconjugate dose did not significantly alter either efficacy or antigen expression. CONCLUSION: Immunoconjugate delivered across the BBB was effective against antigen-positive tumor cells, but there was not an effective chemical bystander effect against antigen-negative tumor cells.

KW - Blood-brain barrier

KW - Brain tumor

KW - Doxorubicin

KW - Immunoconjugate

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