Mechanisms of resistance to low-dose metronomic cyclophosphamide

13079 Background: It has been postulated that antiangiogenic therapies are less susceptible to acquired resistance compared to conventional treatment strategies, which target genetically unstable tumor cells. However, resistance is commonly seen (pre)clinically. A better understanding of the underlying mechanisms is clearly needed to improve such therapies. Methods: We studied mechanisms of acquired resistance to low-dose metronomic (LDM) cyclophosphamide (CTX), the continuous or frequent administration of comparatively low doses of CTX with no extended breaks resulting primarily in antiangiogenic effects, by using LDM CTX relapsed/resistant variants obtained during prolonged in vivo therapy from the human prostate cancer cell line PC-3, which initially is highly responsive. The variants were analyzed for their growth characteristics, angiogenic “phenotype” and impact on circulating endothelial cells (CEC)/endothelial cell progenitors (CEP). Furthermore, we obtained microvessel density (MVD) counts of cor...