Inhibition of tumor angiogenesis by oral etoposide

Abstract

Abstract. the chemotherapeutic agent etoposide is a topoisomerase ii inhibitor widely used for cancer therapy. low-dose oral etoposide, administered at close regular intervals, has potent anti-tumor activity in patients who are refractory to intravenous etoposide; however, the mechanism remains unclear. Since endothelial cells may be more sensitive than tumor cells to chemotherapy agents, we determined the effects of etoposide alone and in combination with oral cyclooxygenase-2 inhibitors and peroxisome-proliferator activated receptor γ ligands on angiogenesis and tumor growth in xenograft tumor models. Optimal anti-angiogenic (metronomic) and anti-tumor doses of etoposide on angiogenesis, primary tumor growth and metastasis were established alone and in combination therapy. Etoposide inhibited endothelial and tumor cell proliferation, decreased vascular endothelial growth factor (VEGF) production by tumor cells and suppressed endothelial tube formation at non-cytotoxic concentrations. in our in vivo studies, oral etoposide inhibited fibroblast growth factor 2 and VEGF-induced corneal neovascularization, VEGF-induced vascular permeability and increased levels of the endogenous angiogenesis inhibitor endostatin in mice. in addition, etoposide inhibited lewis lung carcinoma (llc) and human glioblastoma (u87) primary tumor growth as well as spontaneous lung metastasis in a llc resection model. Furthermore, etoposide had synergistic anti-tumor activity in combination with celecoxib and rosiglitazone, which are also oral anti-angiogenic and anti-tumor agents. Etoposide inhibits angiogenesis in vitro and in vivo by indirect and direct mechanisms of action. combining etoposide with celecoxib and rosiglitazone increases its efficacy and merits further investigation in future clinical trials to determine the potential usefulness of etoposide in combinatory anti-angiogenic chemotherapy.

Regulation of inflammation in cancer by eicosanoids

“…Coussens et al described, in a seminal publication, a genetically engineered mouse model demonstrating inflammation is critical for carcinogenesis (38). We have previously demonstrated that anti-inflammatory drugs such as PPAR ligands and COX-2 inhibitors can inhibit tumor growth by suppressing inflammation and angiogenesis (39-43). …”

Can combination metronomic therapy overcome chemoresistance in cholangiocarcinoma? A literature review

“…[30] Thus, addition of celecoxib may remarkably increase the drug sensitivity of CCa cells to chemotherapy drugs like cyclophosphamide [30] and etoposide. [31] Our patient may have achieved long-term remission through this mechanism. The anticancer agent etoposide was added, keeping in mind the fact that oral etoposide has already been used in palliative regimens in various adult and pediatric solid tumors.…”

“…The anticancer agent etoposide was added, keeping in mind the fact that oral etoposide has already been used in palliative regimens in various adult and pediatric solid tumors. [31] Etoposide is also antiangiogenic and is synergestic when given with celecoxib. [31] Also, as many CCa patients may have abnormal liver function tests (LFTs), etoposide would be a relatively safer drug to be given in such settings.…”

“…[31] Etoposide is also antiangiogenic and is synergestic when given with celecoxib. [31] Also, as many CCa patients may have abnormal liver function tests (LFTs), etoposide would be a relatively safer drug to be given in such settings. Cyclophosphamide additionally depletes T-regs and is also antiangiogenic.…”

Treatment for recurrent medulloblastoma with intrathecal liposomal cytarabine and systemic metronomic combination therapy

“…This tumor has been shown to express vascular endothelial growth factor receptor 2 [20]. Celecoxib [21] and etoposide [22,23] are shown to have an effect on medulloblastoma in vitro and in mice. Thalidomide has not been used in murine medulloblastoma studies due to its different metabolism in mice.…”