Kamat Aparna A, Kim Tae Jin, Landen Charles N, Lu Chunhua, Han Liz Y, Lin Yvonne G, Merritt William M, Thaker Premal H, Gershenson David M, Bischoff Farideh Z, Heymach John V, Jaffe Robert B, Coleman Robert L, Sood Anil K
Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Cancer Res. 2007 Jan 1;67(1):281-8. doi: 10.1158/0008-5472.CAN-06-3282.
Metronomic chemotherapy is the frequent administration of low doses of chemotherapeutic agents targeting tumor-associated endothelial cells. We examined the efficacy of metronomic taxanes alone and in combination with AEE788-a dual epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) inhibitor-in an orthotopic mouse model of ovarian cancer. Growth-modulating effects of metronomic and maximum tolerated dose (MTD) regimens on overall survival were tested in vivo using both chemotherapy-sensitive (HeyA8 and SKOV3ip1) and chemotherapy-resistant (HeyA8-MDR) models. Treated tumors were stained for microvessel density (CD31), proliferation index (proliferating cell nuclear antigen), and apoptosis (terminal deoxyribonucleotide transferase-mediated nick-end labeling). The cytotoxic effects of MTD and metronomic dosing were tested with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Effects of metronomic regimens on circulating endothelial precursors (CEP) and tumor-specific cell-free DNA levels were assessed. In vivo, metronomic docetaxel resulted in significant reduction of tumor growth in the taxane-sensitive cell lines, whereas metronomic docetaxel plus AEE788 had an additive effect resulting in significant prolongation in survival. Combination therapy was effective even in the taxane-resistant model. Metronomic chemotherapy alone and combined with AEE788 resulted in a decrease in the proliferative index and microvessel density of treated tumors, whereas combination therapy increased the apoptotic index (P < 0.001). In vitro, metronomic taxanes caused endothelial cell toxicity at 10- to 100-fold lower concentrations compared with MTD dosing. Metronomic regimens inhibited mobilization of CEPs (P < 0.05) and led to a decrease in cell-free DNA levels (P < 0.05). Our results suggest that metronomic taxane chemotherapy with dual EGFR and VEGFR inhibition is highly efficacious and should be considered for future clinical trials.
节拍化疗是指频繁给予低剂量化疗药物，以靶向肿瘤相关内皮细胞。我们在卵巢癌原位小鼠模型中研究了单药节拍紫杉烷以及与AEE788（一种双表皮生长因子受体（EGFR）和血管内皮生长因子受体（VEGFR）抑制剂）联合使用的疗效。使用化疗敏感模型（HeyA8和SKOV3ip1）和化疗耐药模型（HeyA8-MDR）在体内测试了节拍化疗方案和最大耐受剂量（MTD）方案对总生存期的生长调节作用。对治疗后的肿瘤进行微血管密度（CD31）、增殖指数（增殖细胞核抗原）和凋亡（末端脱氧核苷酸转移酶介导的缺口末端标记）染色。用3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴盐试验测试MTD和节拍给药的细胞毒性作用。评估节拍化疗方案对循环内皮祖细胞（CEP）和肿瘤特异性游离DNA水平的影响。在体内，节拍多西他赛导致紫杉烷敏感细胞系中的肿瘤生长显著减少，而节拍多西他赛加AEE788具有相加作用，导致生存期显著延长。联合治疗即使在紫杉烷耐药模型中也有效。单独的节拍化疗以及与AEE788联合使用均导致治疗后肿瘤的增殖指数和微血管密度降低，而联合治疗增加了凋亡指数（P<0.001）。在体外，与MTD给药相比，节拍紫杉烷在浓度低10至100倍时即可引起内皮细胞毒性。节拍化疗方案抑制了CEP的动员（P<0.05），并导致游离DNA水平降低（P<0.05）。我们的结果表明，联合EGFR和VEGFR抑制的节拍紫杉烷化疗非常有效，应考虑用于未来的临床试验。
