Abstract
The vascular disrupting agent combretastatin A-4 disodium phosphate (CA4P) induces fluctuations in peripheral blood neutrophil concentration. Because neutrophils have the potential to induce both vascular damage and angiogenesis we analyzed neutrophil involvement in the anti-tumoral effects of CA4P in C3H mammary carcinomas in CDF1 mice and in SCCVII squamous cell carcinomas in C3H/HeN mice. Flow cytometry analyses of peripheral blood before and up to 144 h after CA4P administration (25 and 250 mg/kg) revealed a decrease 1 h after treatment, followed by an early (3–6 h) and a late (>72 h) increase in the granulocyte concentration. We suggest that the early increase (3–6 h) in granulocyte concentration was caused by the initial decrease at 1 h and found that the late increase was associated with tumor size, and hence independent of CA4P. No alterations in neutrophil infiltration into the C3H tumor after CA4P treatment (25 and 250 mg/kg) were found. Correspondingly, neutrophil depletion in vivo, using an anti-neutrophil antibody, followed by CA4P treatment (25 mg/kg) did not increase the necrotic fraction in C3H tumors significantly. However, by increasing the CA4P dose to 250 mg/kg we found a significant increase of 359% in necrotic fraction when compared to neutrophil-depleted mice; in mice with no neutrophil depletion CA4P induced an 89% change indicating that the presence of neutrophils reduced the effect of CA4P. In contrast, neither CA4P nor 1A8 affected the necrotic fraction in the SCCVII tumors significantly. Hence, we suggest that the initial decrease in granulocyte concentration was caused by non-tumor-specific recruitment of neutrophils and that neutrophils may attenuate CA4P-mediated anti-tumor effect in some tumor models.
Highlights
Vascular disrupting agents are drugs that target the existing vasculature in tumors [1,2]
Using a Kruskal-Wallis One Way Analysis of Variance on Ranks to compare changes over time we found a significant increase in the number of granulocytes in tumor-bearing mice 72 h after treatment (CA4P dose of 25 mg/kg) 144 h (CA4P dose of 250 mg/kg) after treatment compared to t = 0 in each group
Similar to what we found in the CDF1 mice, we observed a significant decrease in the granulocyte concentration 1 h after treatment with 25 mg/kg Combretastatin A-4 disodium phosphate (CA4P) compared to the granulocyte concentration in mice treated with PBS (Student’s ttest: p,0.001)
Summary
Vascular disrupting agents are drugs that target the existing vasculature in tumors [1,2]. CA4P has undergone testing both as a solitary agent [17,18,19] and in combination with other therapies [20,21] One of those clinical studies reported an increase in the number of granulocytes in peripheral blood 4 and 6 h after CA4P treatment [19], but the significance of this effect is not clear. Yang and co-workers showed that granulocytes derived from tumor bearing mice promote angiogenesis, reduce tumor necrosis, and enhance tumor growth by regulating bioavailability of VEGF [23]. Consistent with both scenarios a recent study in mice further confirmed that neutrophils present in tumors are capable of being either pro- or antitumorigenic dependent on the tumor microenvironment [24]. We determined whether the observed changes could have any influence on the anti-tumor activity of CA4P
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