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_6 label "Selventa" provenance.
_5 value "Therefore, the apoptotic effects of cytotoxic chemotherapy on proliferating vascular endothelium could contribute to the anti-tumor efficacy of chemotherapy in vivo. While it is relatively simple, however, to study chemotherapy-induced apoptosis of endothelial cells or tumor cells separately in vitro, it is not trivial to analyze apoptosis in these two populations when they are crowded together in a tumor. Browder et al. approached this problem by carrying out animal experiments in which the apoptotic effect of cytotoxic chemotherapy on endothelial cells in a tumor bed was dissociated from the apoptotic effect of cytotoxic chemotherapy on tumor cells supported by these endothelial cells [35]. Browder et al. hypothesized, that the tradition of administering chemotherapy at maximum tolerated dose (MTD), required a treatment-free interval to allow recovery of the bone marrow and gastrointestinal tract. During the treatment-free interval, microvascular endothelial cells in the tumor bed could resume their proliferation and support tumor regrowth. When tumor-bearing mice were treated with cyclophosphamide at a conventional maximum tolerated dose followed by a 21-day interval to rescue bone marrow, ('conventional schedule'), tumors recurred after each cycle. All animals eventually died of large tumors which had a diminished response to cyclophosphamide after each cycle, i.e. the tumors developed acquired drug resistance. In contrast, if cyclophosphamide was administered more frequently and at lower doses ('antiangiogenic schedule'), without a prolonged treatment-free interval, all tumors regressed and all animals survived without bone marrow suppression or other toxicity. Then the tumors were made drug-resistant to cyclophosphamide. On the 'conventional schedule', animals died even more rapidly with large tumors as drug resistant tumor cells continued to proliferate unaffected by cyclophosphamide. However, the 'antiangiogenic schedule' significantly inhibited tumor growth, but there was still very slow tumor growth. It was not possible to raise the low dose of cyclophosphamide to a level sufficient to induce apoptosis of the remaining endothelial cells in the tumor bed, without provoking bone marrow suppression. Therefore, a low dose of a pure angiogenesis inhibitor, TNP-470 was added. This inhibitor by itself could not slow this tumor by more than 65%. However, when combined with cyclophosphamide on the antiangiogenic schedule, there was complete tumor regression and long-term survival in all but one animal. Immunohistochemical analysis (Fig. 3) revealed extensive endothelial apoptosis that preceded tumor cell apoptosis by 4-5 days, despite the fact that the tumor cells were resistant to cyclophosphamide and not directly affected by TNP-470. This experiment reveals an endothelial-dependence of cytotoxic chemotherapy that is concealed before tumor cells have acquired drug resistance. Klement et al. obtained similar results by administering continuous low dose vinblastine to tumor-bearing mice in combination with a VEGF receptor antibody [36]. Furthermore, these results might also help to explain why some patients who receive long-term maintenance or even palliative chemotherapy have stable disease beyond the time that the tumor would have been expected to develop drug resistance. Patients with slow-growing cancers who are on 'antiangiogenic scheduling' of chemotherapy involving continuous infusion 5-fluorouracil [37-39], weekly paclitaxel [40,41], or daily oral etoposide [42-44], 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 [45], but the two terms do not have precisely the same meaning. 'Antiangiogenic chemotherapy' signifies that the target of the chemotherapy is microvascular endothelium in the tumor b..." provenance.
_5 wasQuotedFrom 12654259 provenance.
assertion hadPrimarySource 12654259 provenance.
large_corpus.bel title "BEL Framework Large Corpus Document" provenance.
large_corpus.bel description "Approximately 61,000 statements." provenance.
assertion wasDerivedFrom _5 provenance.
assertion wasDerivedFrom large_corpus.bel provenance.
large_corpus.bel authoredBy _6 provenance.
large_corpus.bel version "20131211" provenance.