Abstract
Antiangiogenic therapy is theoretically a promising anticancer approach but does not always produce significant tumor control. Combinations of antiangiogenic therapies are therefore being investigated as strategies to enhance clinical benefit. Common targets for angiogenic blockade include endothelial specific receptors, such as Tie2/Tek, which signal blood vessel stabilization via recruitment and maturation of pericytes. Here, we report on the effects of targeted Tie2 antiangiogenic therapy (TekdeltaFc) in combination with nontargeted metronomic cyclophosphamide (LDM CTX) (reported to also act in antiangiogenic fashion) in xenografted human melanoma. Individually, these therapies showed transient antitumor activity, but, in combination, there was no significant reduction in tumor growth. In addition, while TekdeltaFc caused the expected increased pericyte coverage in treated blood vessels, LDM CTX alone or in combination with TekdeltaFc resulted in increased levels of VEGF production. Collectively, our data highlight the complexity of molecular interactions that may take place when antiangiogenic regimens are combined.
Highlights
Cytotoxic chemotherapeutic drugs may have antiangiogenic properties when administered metronomically at doses significantly lower than the maximum tolerated dose (MTD) and as such appear to have less severe or even absent cytotoxic side effects [1]
To determine if the response to targeted antiangiogenic therapy such as Tie2 inhibition can be enhanced by nontargeted antiangiogenic therapy such as LDM CTX, we examined the impact of this combined approach on human malignant melanoma cancer cell xenografts
There was no additive effect when CTX LDM and TekdeltaFc were combined, as this dual target antiangiogenic regime had no significant effect on tumor growth compared to control at any time point (Figure 1; P > 0.05)
Summary
Cytotoxic chemotherapeutic drugs may have antiangiogenic properties when administered metronomically at doses significantly lower than the maximum tolerated dose (MTD) and as such appear to have less severe or even absent cytotoxic side effects [1]. The antitumor effects of cancers treated with LDM chemotherapy are even more pronounced when combined with an antiangiogenic inhibitor that targets endothelial cells [9, 10]. Tie receptors are primarily found on endothelial cells and are constitutively expressed in normal vasculature [11] It was surprising when our laboratory identified blood vessels within human cancers that lacked Tie expression. We hypothesized that the tumor microenvironment is at least partially responsible for the lack of Tie expression observed in malignant melanoma blood vessels and investigated the possibility that Tie heterogeneity is due to severe hypoxia or hypoglycemia. Recent publications suggest a clear advantage of simultaneously using multiple antiangiogenic therapies in combination with metronomic, low-dose chemotherapy, targeting more than one endothelial cell signaling pathway [5, 21, 22]. To determine if the response to targeted antiangiogenic therapy such as Tie inhibition can be enhanced by nontargeted antiangiogenic therapy such as LDM CTX, we examined the impact of this combined approach on human malignant melanoma cancer cell xenografts
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