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In Reply

Department of Medical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands

In their letter, Shaked et al discuss the nature and origin of the circulating endothelial cells (CECs) we quantified during the phase I trial we performed with the vascular targeting agent ZD6126.¹ Identification and quantification of CECs may be used to answer various scientific questions. To understand the contribution of CEC or endothelial progenitor cells (EPC) to tumor progression, it is important to have a detailed phenotypical analysis of the various types of circulating endothelial cells. There are currently many studies both preclinical and clinical that investigate this concept and there is no definitive answer yet. CECs are also used as potential surrogate markers for treatment efficacy of antivascular agents. These agents may be divided in vascular targeting (or vascular disrupting) agents or antiangiogenic agents. In our study, we anticipated that ZD6126 would cause release of vascular endothelial cells. Based on in vitro studies, proliferating endothelial cells were considered more sensitive to this agent than resting endothelial cells. We therefore selected a pan-endothelial marker, CD146, and used magnetic beads conjugated to an anti-CD146 antibody as the assay of choice to quantify the CEC.² In contrast to what Shaked et al suggest in their letter, this assay allowed us to select for viable cells and to exclude dead or apoptotic cells.³ This method makes it likely that these cells were recently released into the circulation. Moreover, the size assessment allowed an additional discrimination with other circulating mononuclear cells. The purpose of our exploratory analysis was to correlate treatment of ZD6126 with an increase in CD146 positive cells. We found that there was a temporal relationship between peak levels of ZD6126 and the subsequent increase in CEC. This finding suggests that ZD6126 has a direct effect on the vasculature. The observed cardiovascular adverse effects are in line with this assumption. However, using this assay we cannot exclude the contribution of other cell types or EPC to the observed increase in cell numbers. Our exploratory analysis provides a basis to study the increase in CEC during treatment with vascular targeting agents in more detail. We agree with Shaked et al that in future studies specific attention should be given to the origin of these cells. Because the magnetic bead assay is laborious, flow cytometry may be the preferred assay to measure CEC/EPC. Finally, it is important to realize that the value of CEC or EPC as a prognostic marker can only be determined in randomized controlled trials.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Beerepoot LV, Radema SA, Witteveen EO, et al: Phase I clinical evaluation of weekly administration of the novel vascular-targeting agent, ZD6126, in patients with solid tumors. J Clin Oncol 24:1491-1498, 2006[Abstract/Free Full Text]

2. Mutin M, Canavy I, Blann A, et al: Direct evidence of endothelial injury in acute myocardial infarction and unstable angina by demonstration of circulating endothelial cells. Blood 93:2951-2958, 1999[Abstract/Free Full Text]

3. Beerepoot LV, Mehra N, Vermaat JS, et al: Increased levels of viable circulating endothelial cells are an indicator of progressive disease in cancer patients. Ann Oncol 15:139-145, 2004[Abstract/Free Full Text]

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Beerepoot, L. V. Articles by Voest, E. E. Search for Related Content PubMed Articles by Beerepoot, L. V. Articles by Voest, E. E. Social Bookmarking                            What's this?