Combretastatin A-4-phosphate effectively increases tumor retention of the therapeutic antibody, 131I-A5B7, even at doses that are sub-optimal for vascular shut-down

  • Authors:
    • Katharine J. Lankester
    • Ross J. Maxwell
    • R. Barbara Pedley
    • Jason L. Dearling
    • Uzma A. Qureshi
    • Ethaar El-Emir
    • Sally A. Hill
    • Gillian M. Tozer
  • View Affiliations

  • Published online on: February 1, 2007     https://doi.org/10.3892/ijo.30.2.453
  • Pages: 453-460
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Abstract

Radioimmunotherapy using 131I-A5B7, an anti-CEA antibody, in combination with the vascular disrupting agent, combretastatin A4-phosphate (CA-4-P, 200 mg/kg), has produced tumor cures in SW1222 colorectal xenografts. CA-4-P causes acute tumor blood vessel shutdown, which can be monitored in clinical trials using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). The purpose of this study was to determine the magnitude of the anti-vascular effect of CA-4-P in the SW1222 tumor, at 200 mg/kg and at lower, more clinically relevant doses, using conventional assays; relate effects to changes in DCE-MRI parameters and determine the corresponding effects on tumor retention of 131I-A5B7. The tumor vascular effects of 30, 100 and 200 mg/kg CA-4-P were determined, at 4- and 24-h post-treatment, using DCE-MRI, uptake of Hoechst 33342 for tumor vascular volume and conventional histology for necrosis. The effect of CA-4-P on tumor and normal tissue 131I-A5B7 retention was also determined. A significant reduction in tumor DCE-MRI kinetic parameters, the initial area under the contrast agent concentration time curve (IAUGC) and the transfer constant (Ktrans), was demonstrated at 4 h after CA-4-P, for all dose levels. These effects persisted for at least 24 h for the 200 mg/kg group but not for lower doses. A similar pattern was seen for vascular volume and necrosis. Despite this dose response, all three dose levels increased tumor retention of radio labeled antibody to a similar degree. These results demonstrate that moderate tumor blood flow reduction following antibody administration is sufficient to improve tumor antibody retention. This is encouraging for the combination of CA-4-P and 131I-A5B7 in clinical trials.

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February 2007
Volume 30 Issue 2

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Lankester KJ, Maxwell RJ, Pedley RB, Dearling JL, Qureshi UA, El-Emir E, Hill SA and Tozer GM: Combretastatin A-4-phosphate effectively increases tumor retention of the therapeutic antibody, 131I-A5B7, even at doses that are sub-optimal for vascular shut-down. Int J Oncol 30: 453-460, 2007
APA
Lankester, K.J., Maxwell, R.J., Pedley, R.B., Dearling, J.L., Qureshi, U.A., El-Emir, E. ... Tozer, G.M. (2007). Combretastatin A-4-phosphate effectively increases tumor retention of the therapeutic antibody, 131I-A5B7, even at doses that are sub-optimal for vascular shut-down. International Journal of Oncology, 30, 453-460. https://doi.org/10.3892/ijo.30.2.453
MLA
Lankester, K. J., Maxwell, R. J., Pedley, R. B., Dearling, J. L., Qureshi, U. A., El-Emir, E., Hill, S. A., Tozer, G. M."Combretastatin A-4-phosphate effectively increases tumor retention of the therapeutic antibody, 131I-A5B7, even at doses that are sub-optimal for vascular shut-down". International Journal of Oncology 30.2 (2007): 453-460.
Chicago
Lankester, K. J., Maxwell, R. J., Pedley, R. B., Dearling, J. L., Qureshi, U. A., El-Emir, E., Hill, S. A., Tozer, G. M."Combretastatin A-4-phosphate effectively increases tumor retention of the therapeutic antibody, 131I-A5B7, even at doses that are sub-optimal for vascular shut-down". International Journal of Oncology 30, no. 2 (2007): 453-460. https://doi.org/10.3892/ijo.30.2.453