Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity

Low-dose metronomic cyclophosphamide treatment mediates ischemia-dependent K-ras mutation in colorectal carcinoma xenografts

“…Despite effective angiogenic blockade, increased tumor progression has previously been reported in xenograft studies of experimental tumor growth (Klement et al, 2000;Emmenegger et al, 2006). These observations, together with the results of clinical trials using antiangiogenic agents (Yang et al, 2003;Hurwitz et al, 2004;Miller et al, 2005a, b;Motzer and Bukowski, 2006;Varker et al, 2007) suggest a more complex impact of this treatment modality than previously anticipated.…”

“…In particular, bevacuzimab/avastin, a humanized monoclonal-neutralizing antibody directed against vascular endothelial growth factor has since 2004 become incorporated into the first-line therapies in metastatic colorectal carcinoma (CRC) (Hurwitz et al, 2004) and other malignancies (Gasparini et al, 2005). In addition to such targeted antiangiogenic agents designed to obliterate a well-defined molecular mechanism (for example, vascular endothelial growth factor/vascular endothelial growth factor receptor pathway), blood vessel inhibitory properties have also been uncovered in drugs with ostensibly unrelated activities, including cytotoxic anticancer chemotherapeutics (Browder et al, 2000;Klement et al, 2000). Studies with cyclophosphamide and several other agents revealed that when administered at low but frequent (metronomic) doses, they selectively target growing endothelial cells and block formation of tumor blood vessels (Browder et al, 2000;Klement et al, 2000).…”

Ablation of microvessels in vivo upon dimerization of iCaspase-9

“…These anti-angiogenic approaches have shown efficacy by themselves or in combination with other therapeutic modalities for the inhibition of tumor growth in animal models. [15][16][17] The anti-angiogenic effect is mediated at least in part by the suppression of intracellular pro-survival molecules that act to repress the activation of apical caspases and apoptosis in endothelial cells. However, the engagement of parallel endothelial cell survival pathways may be sufficient to re-establish tissue vascularization and resistance to anti-angiogenic therapies.…”

Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11

“…Several studies have shown that AAT potentiates the efficacy of standard anticancer drugs with enhanced delay of tumour growth (Teicher et al, 1992(Teicher et al, , 1994Sweeney et al, 2001), stimulating interest in combining these two treatment modalities. Also, low-dose (metronomic) regimens of standard chemotherapy can have clear preclinical activity without significant toxicity, and when combined with AAT may lead to full and sustained regressions (Browder et al, 2000;Klement et al, 2000;Man et al, 2002). One study has suggested that pretreatment with the antiangiogenic drug TNP-470 and minocycline results in increased intratumoral drug levels of platinum (Teicher et al, 1995a).…”