{"id":892,"date":"2020-02-18T10:59:28","date_gmt":"2020-02-18T05:29:28","guid":{"rendered":"https:\/\/medicineplexus.com\/?p=892"},"modified":"2020-02-18T10:59:28","modified_gmt":"2020-02-18T05:29:28","slug":"metronomic-chemotherapy","status":"publish","type":"post","link":"https:\/\/medicineplexus.com\/metronomic-chemotherapy\/","title":{"rendered":"Metronomic Chemotherapy"},"content":{"rendered":"\n
Metronomic Chemotherapy<\/strong><\/p>\n\n\n\n Cancer<\/strong><\/p>\n\n\n\n Current challenges to Maximum Tolerated Dose (MTD) Chemotherapy<\/strong><\/p>\n\n\n\n (maximum tolerated dose is determined in clinical trials by testing increasing doses on different groups of people until the highest dose with acceptable side effects is found)<\/strong><\/p>\n\n\n\n What would be the advantage of using chemotherapeutics as possible angiogenesis inhibitors?<\/strong><\/p>\n\n\n\n Why not routine angiogenesis inhibitors?<\/strong><\/p>\n\n\n\n Shortcomings of anti-vascular tumor therapy:<\/p>\n\n\n\n (i) most tumors are inherently resistant to VEGFi and other anti-vascular therapies used alone;<\/p>\n\n\n\n (ii) even when used in combinations that increase the initial response rate, responsive tumors typically develop acquired resistance within a few months; and<\/p>\n\n\n\n (iii) Adjuvant use of these agents did not increase cure rates.<\/p>\n\n\n\n However, the frequent and sustained use of low doses of conventional chemotherapeutics mimics the long-term antiangiogenic activities of VEGFi.<\/strong><\/p>\n\n\n\n Klement et al.<\/em>, demonstrated that continuous low\u2011dose vinblastine combined with anti\u2011VEGF antibody (VEGF: Vascular endothelial growth factor) caused a significantly greater regression of xenograft tumors as a result of reduced tumor vascularity and angiogenesis.<\/p>\n\n\n\n Concept of Metronomic Chemotherapy<\/strong><\/p>\n\n\n\n Metronomic chemotherapy is the chronic administration of chemotherapy at low, minimally toxic doses on a frequent schedule of administration, with no prolonged drug-free breaks.<\/strong><\/p>\n\n\n\n Mechanism of action<\/strong><\/p>\n\n\n\n Metronomic chemotherapy induces important antiangiogenic effects (inhibition of endothelial cell proliferation, migration and morphogenesis, decrease in mobilization and viability of endothelial progenitor cells and increase in Thrombospondin-1 expression), resulting in a reduction of the tumor vasculature.<\/p>\n\n\n\n In addition, metronomic chemotherapy also decreases the number and activity of regulatory T cells (TREG) and may promote dendritic cell maturation, leading to (re)activation of an anticancer immune response, in part mediated by cytotoxic T cells and natural killer (NK) cells.<\/p>\n\n\n\n 4 D Effect<\/strong><\/p>\n\n\n\n Andre et al., <\/em><\/strong>have postulated a \u2018drug\u2011driven dependency\/ deprivation<\/strong>\u2019<\/strong> or a 4\u2011dimensional (4D) phenomenon<\/p>\n\n\n\n Criteria of an anti-angiogenic agent for MCT<\/strong><\/p>\n\n\n\n Which Patients Are Candidates?<\/strong><\/p>\n\n\n\n When to use?<\/strong><\/p>\n\n\n\n Palliative purposes in relapse\/refractory diseases and metastatic cases<\/p>\n\n\n\n or<\/p>\n\n\n\n Toxicity<\/strong><\/p>\n\n\n\n Biomarkers for evaluation<\/strong><\/p>\n\n\n\n Biomarkers to indicate achievement of pharmacodynamic effects are important to determine the optimal metronomic dose (OMD) of cytotoxics.<\/p>\n\n\n\n MTD determination is easily established with routine laboratory tests and clinical assessments, OMD determination faces significant challenges<\/p>\n\n\n\n the circulating endothelial progenitor cells (ceps) that are considered to be an alternative source for some of the endothelial cells of newly formed blood vessels represent a subset of immature vegfr2-positive cecs also found in peripheral blood<\/p>\n\n\n\nConventional Chemotherapy<\/strong><\/strong><\/td> Metronomic Chemotherapy<\/strong><\/strong><\/td><\/tr> Maximum tolerated doses(MTD) used<\/td> Lower dose than MTD<\/td><\/tr> Therapy at defined intervals depending on recovery of bone marrow. Eg: 3 weekly<\/td> Dosing frequency is continuous. Eg: Weekly, daily, alternate days<\/td><\/tr> Rise and fall of plasma conc<\/td> Sustained plasma conc<\/td><\/tr> Targets proliferating tumor cells<\/td> Targets endothelial cells of vasculature of the tumour<\/td><\/tr> Toxicity concern<\/td> Less toxicity<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n