Chapter 080. Cancer Cell Biology and Angiogenesis (Part 18)

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Antiangiogenic Therapy Understanding the molecular mechanisms that regulate tumor angiogenesis may provide unique opportunities for cancer treatment. Acquired drug resistance of tumor cells due to their high intrinsic mutation rate is a major cause of treatment failure in human cancers. ECs comprising the tumor vasculature are genetically stable and do not share genetic changes with tumor cells; the EC apoptosis pathways are therefore intact. Each EC of a tumor vessel helps provide nourishment to many tumor cells, and although tumor angiogenesis can be driven by a number of exogenous proangiogenic stimuli, experimental data indicate that at least in some...

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Chapter 080. Cancer Cell Biology and Angiogenesis (Part 18) Antiangiogenic Therapy Understanding the molecular mechanisms that regulate tumor angiogenesis may provide unique opportunities for cancer treatment. Acquired drug resistance of tumor cells due to their high intrinsic mutation rate is a major cause of treatment failure in human cancers. ECs comprising the tumor vasculature are genetically stable and do not share genetic changes with tumor cells; the EC apoptosis pathways are therefore intact. Each EC of a tumor vessel helps provide nourishment to many tumor cells, and although tumor angiogenesis can be driven by a number of exogenous proangiogenic stimuli, experimental data indicate that at least in some tumor types, blockade of a single growth factor (e.g., VEGF) may inhibit tumor-induced vascular growth. Angiogenesis inhibitors function by
targeting the critical molecular pathways involved in EC proliferation, migration, and/or survival, many of which are unique to the activated endothelium in tumors. Inhibition of growth factor and adhesion-dependent signaling pathways can induce EC apoptosis with concomitant inhibition of tumor growth. Different types of tumors use distinct molecular mechanisms to activate the angiogenic switch. Therefore, it is doubtful that a single antiangiogenic strategy will suffice for all human cancers; rather, a number of agents will be needed, each responding to distinct programs of angiogenesis used by different human cancers. Four randomized phase III clinical trials have demonstrated that the addition of bevacizumab (Avastin; a humanized monoclonal antibody that binds and inhibits VEGF) to chemotherapy results in significantly improved response rates, progression-free survival, and overall survival when compared to treatment with chemotherapy alone (Table 80-3). This effect was shown in the first-line treatment of patients with advanced colon, lung, and breast cancers, and in the second-line treatment of colon cancer. However, not all trials have been positive; in previously treated breast cancer, the addition of bevacizumab to capecitabine (an oral fluoropyrimidine) did not increase efficacy, and in previously untreated pancreatic cancer, bevacizumab did not enhance the efficacy of gemcitabine. Table 80-3 Randomized Phase III Clinical Trials Demonstrating the Efficacy of Bevacizumab in Combination with Chemotherapy for the
Treatment of Advanced Cancers Tu Stage Previ Num Chemothe Outc mor Type of Disease ous ber of rapy Regimen ome Treatment Patients Col Metas No 813 Irinotecan Incre on cancer tatic + 5-FU/LV ± ased OS bevacizumab (20.3 vs 15.6 months), PFS (10.6 vs 6.2 months), and RR (44.8 vs 34.8%) Col Metas Seco 829 FOLFOX Incre on cancer tatic nd line; ± bevacizumab ased OS previous (12.9 vs 10.8 irinotecan/5 months), -FU PFS (7.2 vs
4.8 months), RR (21.8 vs 9.2%). Non Metas No 878 Carboplati Incre -small cell tatic num + paclitaxel ased OS lung ± bevacizumab (12.5 vs 10.2 cancer months), (excluding PFS (6.4 vs squamous 4.5 months), histology) RR (27.2 vs 10.0%). Bre Recur No 722 Paclitaxel Incre ast cancer rent or ± bevacizumab ased PFS metastatic (11.0 vs 6.2 months), RR (28 vs 14%). Note: 5-FU, 5-fluorouracil; LV, leucovoran; OS, overall survival; PFS, progression-free survival; RR, response rate; FOLFOX, folinic acid (LV), 5-FU,
and oxaliplatinum.