[Abstract unavailable

SUMMARY Several hypotheses have been proposed to explain how antiangiogenic drugs enhance the treatment efficacy of cytotoxic chemotherapy including impairing the ability of chemotherapy-responsive tumors to regrow after therapy. With respect to the latter, we show that certain chemotherapy drugs, e.g. paclitaxel, can rapidly induce pro-angiogenic bone marrow derived circulating endothelial cell (CEP) mobilization, and subsequent tumor homing, whereas others, e.g. gemcitabine, did not. Acute CEP mobilization was mediated, at least in part, by systemic induction of SDF-1α and could be prevented by various procedures such as treatment with anti-VEGFR2 blocking antibodies or by paclitaxel treatment in CEP-deficient Id-mutant mice, both of which resulted in enhanced anti-tumor effects mediated by paclitaxel, but not gemcitabine.

Low-dose metronomic chemotherapy is a promising therapeutic cancer treatment strategy thought to have an antiangiogenic basis. However, the advantages of reduced toxicity, increased efficacy in some cases, and ability to combine chemotherapy administered long term in this way with targeted therapies can be compromised by the empiricism associated with determining the optimum biologic dose (OBD). Using 4 distinct metronomic chemotherapy regimens in 4 different preclinical tumor models, including a hematologic malignancy, we established the OBD by determining the maximum efficacy associated with minimum or no toxicity. We then found each OBD to be strikingly correlated with the maximum reduction in viable peripheral blood circulating vascular endothelial growth factor receptor 2-positive (VEGFR-2 ؉ ) endothelial precursors (CEPs). These results suggest that CEPs may serve as a pharmacodynamic biomarker to determine the OBD of metronomic chemotherapy regimens. IntroductionThe tumor vasculature has emerged as a clinically validated therapeutic target. 1 In addition to rationally designed, molecularly targeted antiangiogenic drugs such as anti-vascular endothelial growth factor (anti-VEGF) antibodies, 1 many conventional and new therapeutic agents may have antiangiogenic effects that can contribute to their treatment efficacy. 2,3 These agents include chemotherapy drugs, the antiangiogenic efficacy of which appear to be optimized by "metronomic" dosing or the administration of relatively low, nontoxic doses at regular close intervals with no prolonged interruptions. 3-5 Some metronomic regimens can have surprisingly potent antitumor effects in preclinical models compared with respective maximum tolerated dose regimens, despite being less toxic. 4,6,7 This makes it possible to consider combining simultaneously such long-term "maintenance" chemotherapy with targeted antiangiogenic drugs 8,9 or other agents, such as tumor vaccines. 10 Some promising preliminary results have also begun to emerge in small clinical studies using mostly orally administered metronomic chemotherapy-based regimens, 3,11,12 including those in the adjuvant setting for early-stage cancer. 13 However, a significant disadvantage is the empiricism in establishing the optimal biologic dose (OBD) and in monitoring therapeutic activity early during the course of treatment. 3 Using (1) previous observations showing significant and sustained declines in circulating VEGF receptor 2-positive (VEGFR-2 ϩ ) endothelial progenitor cells (CEPs) induced by prolonged daily low-dose metronomic chemotherapy 6 ; (2) preclinical validation of measuring levels of such cells as a surrogate blood-based marker of angiogenesis and targeted antiangiogenic drug activity, including optimal biologic dosing 14 ; and (3) CEP potentially as a marker in the clinic of targeted antiangiogenic drug activity, 15 we assessed whether determining OBD ranges of various chemotherapy drugs is possible using this cellular pharmacodynamic biomarker approach. Specifically, we addressed the q...