Bevacizumab-induced alterations in vascular permeability and drug delivery: A novel approach to augment regional chemotherapy for in-transit melanoma

Ryan S. Turley, Andrew N. Fontanella, James C. Padussis, Hiroaki Toshimitsu, Yoshihiro Tokuhisa, Eugenia H. Cho, Gabi Hanna, Georgia M. Beasley, Christina K. Augustine, Mark W. Dewhirst, Douglas Tyler

Research output: Contribution to journalArticle

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Abstract

Purpose: To investigate whether the systemically administered anti-VEGF monoclonal antibody bevacizumab could improve regional chemotherapy treatment of advanced extremity melanoma by enhancing delivery and tumor uptake of regionally infused melphalan (LPAM). Experimental Design: After treatment with systemic bevacizumab or saline, changes in vascular permeability were determined by spectrophotometric analysis of tumors infused with Evan's blue dye. Changes in vascular structure and tumor hemoglobin-oxygen saturation HbO2 were determined by intravital microscopy and diffuse reflectance spectroscopy, respectively. Rats bearing the low-VEGF secreting DM738 and the high-VEGF secreting DM443 melanoma xenografts underwent isolated limb infusion (ILI) with melphalan (LPAM) or saline via the femoral vessels. The effect of bevacizumab on terminal drug delivery was determined by immunohistochemical analysis of LPAM-DNA adducts in tumor tissues. Results: Single-dose bevacizumab given three days before ILI with LPAM significantly decreased vascular permeability (50.3% in DM443, P < 0.01 and 35% in DM738, P < 0.01) and interstitial fluid pressure (57% in DM443, P < 0.01 and 50% in DM738, P = 0.01). HbO2 decreased from baseline in mice following treatment with bevacizumab. Systemic bevacizumab significantly enhanced tumor response to ILI with LPAM in two melanoma xenografts, DM443 and DM738, increasing quadrupling time 37% and 113%, respectively ( P = 0.03). Immunohistochemical analyses of tumor specimens showed that pretreatment with systemic bevacizumab markedly increased LPAM-DNA adduct formation. Conclusions: Systemic treatment with bevacizumab before regional chemotherapy increases delivery of LPAM to tumor cells and represents a novel way to augment response to regional therapy for advanced extremity melanoma.

Original languageEnglish (US)
Pages (from-to)3328-3339
Number of pages12
JournalClinical Cancer Research
Volume18
Issue number12
DOIs
StatePublished - Jun 15 2012
Externally publishedYes

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Capillary Permeability
Melanoma
Drug Therapy
Extremities
Pharmaceutical Preparations
Neoplasms
Vascular Endothelial Growth Factor A
Melphalan
DNA Adducts
Heterografts
Therapeutics
Evans Blue
Bevacizumab
Extracellular Fluid
Thigh
Blood Vessels
Spectrum Analysis
Hemoglobins
Research Design
Coloring Agents

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Bevacizumab-induced alterations in vascular permeability and drug delivery : A novel approach to augment regional chemotherapy for in-transit melanoma. / Turley, Ryan S.; Fontanella, Andrew N.; Padussis, James C.; Toshimitsu, Hiroaki; Tokuhisa, Yoshihiro; Cho, Eugenia H.; Hanna, Gabi; Beasley, Georgia M.; Augustine, Christina K.; Dewhirst, Mark W.; Tyler, Douglas.

In: Clinical Cancer Research, Vol. 18, No. 12, 15.06.2012, p. 3328-3339.

Research output: Contribution to journalArticle

Turley, RS, Fontanella, AN, Padussis, JC, Toshimitsu, H, Tokuhisa, Y, Cho, EH, Hanna, G, Beasley, GM, Augustine, CK, Dewhirst, MW & Tyler, D 2012, 'Bevacizumab-induced alterations in vascular permeability and drug delivery: A novel approach to augment regional chemotherapy for in-transit melanoma', Clinical Cancer Research, vol. 18, no. 12, pp. 3328-3339. https://doi.org/10.1158/1078-0432.CCR-11-3000
Turley, Ryan S. ; Fontanella, Andrew N. ; Padussis, James C. ; Toshimitsu, Hiroaki ; Tokuhisa, Yoshihiro ; Cho, Eugenia H. ; Hanna, Gabi ; Beasley, Georgia M. ; Augustine, Christina K. ; Dewhirst, Mark W. ; Tyler, Douglas. / Bevacizumab-induced alterations in vascular permeability and drug delivery : A novel approach to augment regional chemotherapy for in-transit melanoma. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 12. pp. 3328-3339.
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abstract = "Purpose: To investigate whether the systemically administered anti-VEGF monoclonal antibody bevacizumab could improve regional chemotherapy treatment of advanced extremity melanoma by enhancing delivery and tumor uptake of regionally infused melphalan (LPAM). Experimental Design: After treatment with systemic bevacizumab or saline, changes in vascular permeability were determined by spectrophotometric analysis of tumors infused with Evan's blue dye. Changes in vascular structure and tumor hemoglobin-oxygen saturation HbO2 were determined by intravital microscopy and diffuse reflectance spectroscopy, respectively. Rats bearing the low-VEGF secreting DM738 and the high-VEGF secreting DM443 melanoma xenografts underwent isolated limb infusion (ILI) with melphalan (LPAM) or saline via the femoral vessels. The effect of bevacizumab on terminal drug delivery was determined by immunohistochemical analysis of LPAM-DNA adducts in tumor tissues. Results: Single-dose bevacizumab given three days before ILI with LPAM significantly decreased vascular permeability (50.3{\%} in DM443, P < 0.01 and 35{\%} in DM738, P < 0.01) and interstitial fluid pressure (57{\%} in DM443, P < 0.01 and 50{\%} in DM738, P = 0.01). HbO2 decreased from baseline in mice following treatment with bevacizumab. Systemic bevacizumab significantly enhanced tumor response to ILI with LPAM in two melanoma xenografts, DM443 and DM738, increasing quadrupling time 37{\%} and 113{\%}, respectively ( P = 0.03). Immunohistochemical analyses of tumor specimens showed that pretreatment with systemic bevacizumab markedly increased LPAM-DNA adduct formation. Conclusions: Systemic treatment with bevacizumab before regional chemotherapy increases delivery of LPAM to tumor cells and represents a novel way to augment response to regional therapy for advanced extremity melanoma.",
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T1 - Bevacizumab-induced alterations in vascular permeability and drug delivery

T2 - A novel approach to augment regional chemotherapy for in-transit melanoma

AU - Turley, Ryan S.

AU - Fontanella, Andrew N.

AU - Padussis, James C.

AU - Toshimitsu, Hiroaki

AU - Tokuhisa, Yoshihiro

AU - Cho, Eugenia H.

AU - Hanna, Gabi

AU - Beasley, Georgia M.

AU - Augustine, Christina K.

AU - Dewhirst, Mark W.

AU - Tyler, Douglas

PY - 2012/6/15

Y1 - 2012/6/15

N2 - Purpose: To investigate whether the systemically administered anti-VEGF monoclonal antibody bevacizumab could improve regional chemotherapy treatment of advanced extremity melanoma by enhancing delivery and tumor uptake of regionally infused melphalan (LPAM). Experimental Design: After treatment with systemic bevacizumab or saline, changes in vascular permeability were determined by spectrophotometric analysis of tumors infused with Evan's blue dye. Changes in vascular structure and tumor hemoglobin-oxygen saturation HbO2 were determined by intravital microscopy and diffuse reflectance spectroscopy, respectively. Rats bearing the low-VEGF secreting DM738 and the high-VEGF secreting DM443 melanoma xenografts underwent isolated limb infusion (ILI) with melphalan (LPAM) or saline via the femoral vessels. The effect of bevacizumab on terminal drug delivery was determined by immunohistochemical analysis of LPAM-DNA adducts in tumor tissues. Results: Single-dose bevacizumab given three days before ILI with LPAM significantly decreased vascular permeability (50.3% in DM443, P < 0.01 and 35% in DM738, P < 0.01) and interstitial fluid pressure (57% in DM443, P < 0.01 and 50% in DM738, P = 0.01). HbO2 decreased from baseline in mice following treatment with bevacizumab. Systemic bevacizumab significantly enhanced tumor response to ILI with LPAM in two melanoma xenografts, DM443 and DM738, increasing quadrupling time 37% and 113%, respectively ( P = 0.03). Immunohistochemical analyses of tumor specimens showed that pretreatment with systemic bevacizumab markedly increased LPAM-DNA adduct formation. Conclusions: Systemic treatment with bevacizumab before regional chemotherapy increases delivery of LPAM to tumor cells and represents a novel way to augment response to regional therapy for advanced extremity melanoma.

AB - Purpose: To investigate whether the systemically administered anti-VEGF monoclonal antibody bevacizumab could improve regional chemotherapy treatment of advanced extremity melanoma by enhancing delivery and tumor uptake of regionally infused melphalan (LPAM). Experimental Design: After treatment with systemic bevacizumab or saline, changes in vascular permeability were determined by spectrophotometric analysis of tumors infused with Evan's blue dye. Changes in vascular structure and tumor hemoglobin-oxygen saturation HbO2 were determined by intravital microscopy and diffuse reflectance spectroscopy, respectively. Rats bearing the low-VEGF secreting DM738 and the high-VEGF secreting DM443 melanoma xenografts underwent isolated limb infusion (ILI) with melphalan (LPAM) or saline via the femoral vessels. The effect of bevacizumab on terminal drug delivery was determined by immunohistochemical analysis of LPAM-DNA adducts in tumor tissues. Results: Single-dose bevacizumab given three days before ILI with LPAM significantly decreased vascular permeability (50.3% in DM443, P < 0.01 and 35% in DM738, P < 0.01) and interstitial fluid pressure (57% in DM443, P < 0.01 and 50% in DM738, P = 0.01). HbO2 decreased from baseline in mice following treatment with bevacizumab. Systemic bevacizumab significantly enhanced tumor response to ILI with LPAM in two melanoma xenografts, DM443 and DM738, increasing quadrupling time 37% and 113%, respectively ( P = 0.03). Immunohistochemical analyses of tumor specimens showed that pretreatment with systemic bevacizumab markedly increased LPAM-DNA adduct formation. Conclusions: Systemic treatment with bevacizumab before regional chemotherapy increases delivery of LPAM to tumor cells and represents a novel way to augment response to regional therapy for advanced extremity melanoma.

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