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Furthermore, TNF inhibitors are not effective in animal models of myeloma or in patients.TNF suppression therefore does not appear to be a major part of thalidomides Secnidazole antiangiogenic activity.Thalidomide does have a direct antiproliferative effect on multiple myeloma cells in vitro, although very high concentrations of thalidomide are required.Nevertheless, this drug might be able to target both cancer cells and vascular endothelial cells.In patients with multiple myeloma, or myelodysplastic syndromes, plasma levels of the proangiogenic proteins, VEGF and bFGF were significantly decreased compared to pretreatment levels.This created a question of whether the clinical eff icacy of thalidomide was mediated entirely or even partly by its antiangiogenic features.While increased microvessel density in bone mar row is associated with relapse in multiple myeloma or with untreated multiple myeloma in vir tually all repor ts to date, microvessel density has not been an effective measure of therapeutic response in many patients with multiple myeloma.Decreased circulating levels of VEGF cor related with thalidomides therapeutic eff icacy in multiple myeloma and other hematologic diseases.However, serum VEGF alone has not been a predictable marker of angiogenesis in other tumors, in part because of the high VEGF content of platelets, and because circulating angiogenesis inhibitors are not taken into account.Chemotherapeutic agents have in fact been shown to have antiangiogenic proper ties in animalmode ls, in addit ion to their ability to inducedi rectcancercell dea th. Pacli taxel, wh ich inh ibitsmic ro tubu le po lymerization, inhibits vascular endothelial cell proliferation, motility and invasiveness in a dosedependent mannerinvitro and tumorang iogenes is in vivo.Secondary effects such as these could contr ibu te to the anti tumore ff icacyof chemo the rapy invivo andmightde layor prevent the acquisition of drugresistance by cancer cells.This could be because chemotherapy is usually administered at the maximum tolerated dose, followed by a treatmentfree interval to allow recovery of bone marrow and gastrointestinal tract cells.During the treatmentfree interval, microvascular endothelial cells in the tumor bed can resume their proliferation and support tumor regrowth.Antiangiogenic chemotherapy wasfirst shown to be effective in tumorbearing mice.Administration of cyclophosphamide at more frequent intervals at an overall lower dose with a brief treatmentfree interval induced sustained apoptosis of endothelial cells in the vascular bed of the tumors, and more effectively controlled growth of drugresistant tumors.These results might also help to explain why some patients who receive longterm maintenance or even palliative chemotherapy have stable disease beyond the time that the tumor would have been Amorolfine hydrochloride expected to develop drug resistance.Patients with slowgrowing cancers who are on antiangiogenic scheduling of chemotherapy involving continuous infusion fluorouracil, weekly paclitaxel, or daily oral etoposide have shown an improved outcome despite the fact that in some of these patients the tumors had already become drug resistant to conventional chemotherapy.Antiangiogenic chemotherapy has also been called metronomic therapy, but the two terms do not have precisely the same meaning.Antiangiogenic chemotherapy signif ies that the target of the chemotherapy is microvascular endothelium in the tumor bed.Metronomic therapy indicates that the schedule of administration is at very regular intervals.Every weeks, lowdose etoposide is substituted for cyclophosphamide.

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