Development of a Resistance-like Phenotype to Sorafenib by Human Hepatocellular Carcinoma Cells Is Reversible and Can Be Delayed by Metronomic UFT Chemotherapy
Development of a Resistance-like Phenotype to Sorafenib by Human Hepatocellular Carcinoma Cells Is Reversible and Can Be Delayed by Metronomic UFT Chemotherapy
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DOI：
10.1593/neo.10804
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发表时间：
2010-11-01
期刊：
影响因子：
4.8
通讯作者：
Kerbel, Robert S.
中科院分区：
文献类型：
--
作者：
Tang, Terence C.;Man, Shan;Kerbel, Robert S.
对抗血管生成药物如索拉非尼的获得性耐药性是一个主要的临床问题。我们研究了索拉非尼耐药的发展，在新的临床前模型的人肝细胞癌（HCC）沿着的策略，以延迟这种耐药与节拍化疗组合。使用对索拉非尼高度反应的人Hep 3B HCC细胞研究了三种不同的异种移植模型，即在严重联合免疫缺陷小鼠中的原位和皮下移植，以及在裸鼠中的原位移植。将人绒毛膜促性腺激素β亚基的互补DNA转染到HCC细胞中，并监测尿中蛋白水平作为肿瘤负荷的替代物。延长的每日治疗，有时中断3至7天的中断期，以允许从索拉非尼剂量30至60 mg/kg的毒性中恢复，直至肿瘤复发的证据。最初有反应的肿瘤似乎在长期每日治疗后发展出耐药样表型（例如，>42天），剂量为30至60 mg/kg。将从进展中的肿瘤建立的细胞系移植到新的宿主中表明，耐药表型没有繁殖。此外，每日节律尿嘧啶+替加氟（UFT，一种口服5-氟尿嘧啶前药）化疗方案与毒性较小的索拉非尼方案（15 mg/kg/天）显著延迟了耐药性的发生（>91天）。总之，索拉非尼耐药样表型的发展是可逆的，节拍UFT加索拉非尼可能是一种有前途的和耐受性良好的治疗，通过延迟这种耐药的出现来增加疗效。
Acquired resistance to antiangiogenic drugs, such as sorafenib, is a major clinical problem. We studied development of a resistance to sorafenib in new preclinical models of human hepatocellular carcinoma (HCC) along with a strategy to delay such resistance-combination with metronomic chemotherapy. Three different xenograft models were studied using human Hep3B HCC cells, which are highly responsive to sorafenib, namely, orthotopic and subcutaneous transplant in severe combined immunodeficient mice, and an orthotopic transplant in nude mice. The complementary DNA for the beta-subunit of human choriogonadotropin was transfected into HCC cells, and urine levels of the protein were monitored as a surrogate of tumor burden. Extended daily treatments, sometimes interrupted by a break period of 3 to 7 days to allow recovery from toxicity at sorafenib doses of 30 to 60 mg/kg, were maintained until and after evidence of tumor relapse. Initially responsive tumors seemed to develop a resistance-like phenotype after long-term daily treatment (e.g., >42 days) at doses of 30 to 60mg/kg. Transplantation of cell lines established from progressing tumors into new hosts showed that the resistant phenotype was not propagated. Furthermore, a regimen of daily metronomic uracil + tegafur (UFT, an oral 5-fluorouracil prodrug) chemotherapy with a less toxic regimen of sorafenib (15 mg/kg per day) significantly delayed the onset of resistance (>91 days). In conclusion, development of a resistance-like phenotype to sorafenib is reversible, and metronomic UFT plus sorafenib may be a promising and well-tolerated treatment for increasing efficacy by delaying emergence of such resistance.