In vivo activity of novel capecitabine regimens alone and with bevacizumab and oxaliplatin in colorectal cancer xenograft models
In vivo activity of novel capecitabine regimens alone and with bevacizumab and oxaliplatin in colorectal cancer xenograft models
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DOI：
10.1158/1535-7163.mct-08-0596
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发表时间：
2009-01-01
影响因子：
5.7
通讯作者：
Higgins, Brian
中科院分区：
文献类型：
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作者：
Kolinsky, Kenneth;Shen, Ben-Quan;Higgins, Brian
将卡培他滨的给药程序从14天开始，7天停止(14/7)改为7天开始，7天停止(7/7)，可能会在结直肠癌移植瘤中实现更高的剂量和更好的抗肿瘤效果。卡培他滨14/7(267或400 mg/kg)和7/7(467或700 mg/kg)方案在荷有HT29结直肠移植瘤的雌性裸鼠体内进行了最佳剂量贝伐单抗(5 mg/kg)和奥沙利铂(6.7 mg/kg)的双联和三联方案研究。在类似的Colo205肿瘤移植模型中，还进行了次最佳剂量的贝伐单抗(2.5 mg/kg)和卡培他滨7/7(360 mg/kg)的额外研究。对10只动物进行了单一治疗和联合治疗，并与车辆对照组进行了比较。在HT29模型中，卡培他滨7/7组的肿瘤生长抑制率和生存期(ILS)显著高于14/7组(P<；0.05)。根据美国国家癌症研究所的标准(25%ILS)，卡培他滨7/7和14/7的额外益处在生物学上是显著的。在卡培他滨7/7中加入贝伐单抗后，与单独使用这两种药物相比，存活率显著提高(P<；0.0001)。加入奥沙利铂后，卡培他滨7/7(肿瘤生长抑制率为100%，ILS为234%)与14/7(分别为95%和81%)联合用药的疗效明显优于卡培他滨。在Colo205模型中，卡培他滨7/7和贝伐单抗的联合治疗比单独使用任何一种药物都能显著提高存活率(P<；0.0001)。总之，在携带中度胸苷磷酸化酶HT29或Colo205的裸鼠移植瘤中，与传统的14/7方案相比，卡培他滨7/7方案允许增加药物输送，极大地改善了单一治疗活性，而没有重大毒性。[摩尔癌症治疗2009；8(1)：75-82]
Modifying the capecitabine dosing schedule from 14 days on, 7 days off (14/7) to 7 days on, 7 days off (7/7) may enable higher doses and improved antitumor efficacy in colorectal cancer xenografts. Capecitabine 14/7 (267 or 400 mg/kg) and 7/7 (467 or 700 mg/kg) schedules in doublet and triplet combinations with optimally dosed bevacizumab (5 mg/kg) and oxaliplatin (6.7 mg/kg) were studied in female athymic nude mice bearing HT29 colorectal xenografts. Additional studies of suboptimally dosed bevacizumab (2.5 mg/kg) and capecitabine 7/7 (360 mg/kg) were done in a similar Colo205 tumor xenograft model. Monotherapy and combination regimens were administered to groups of 10 animals and compared with vehicle controls. In the HT29 model, tumor growth inhibition and increase in life span (ILS) were significantly greater with capecitabine 7/7 than with 14/7 (P < 0.05). The additional benefit of capecitabine 7/7 versus 14/7 was biologically significant according to National Cancer Institute criteria (>25% ILS). Adding bevacizumab to capecitabine 7/7 resulted in significantly greater survival relative to either agent alone (P < 0.0001). When oxaliplatin was added, efficacy was significantly better with the triplet combination including capecitabine 7/7 (tumor growth inhibition > 100% and ILS 234%) compared with 14/7 (95% and 81%, respectively). In the Colo205 model, combination therapy with capecitabine 7/7 plus bevacizumab resulted in significantly greater survival relative to either agent alone (P < 0.0001). In conclusion, in athymic nude mice bearing moderately thymidine phosphorylase - expressing HT29 or Colo205 colorectal xenografts, a capecitabine 7/7 schedule permits increased drug delivery compared with traditional 14/7 regimens, greatly improving monotherapy activity without major toxicity. [Mol Cancer Ther 2009;8(1):75 - 82]