Analysis of acquired resistance to metronomic oral topotecan chemotherapy plus pazopanib after prolonged preclinical potent responsiveness in advanced ovarian cancer.
Analysis of acquired resistance to metronomic oral topotecan chemotherapy plus pazopanib after prolonged preclinical potent responsiveness in advanced ovarian cancer.
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DOI：
10.1007/s10456-014-9422-9
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发表时间：
2014-07
期刊：
影响因子：
9.8
通讯作者：
Kerbel RS
中科院分区：
文献类型：
--
作者：
Cruz-Muñoz W;Di Desidero T;Man S;Xu P;Jaramillo ML;Hashimoto K;Collins C;Banville M;O'Connor-McCourt MD;Kerbel RS
常规最大耐受剂量（MTD）化疗的另一种选择或后续辅助疗法是节奏化疗，即低剂量的常规给药，没有长时间的间断。许多临床前研究表明，在没有明显毒性的情况下，节律化疗可以使患有晚期癌症（包括转移性疾病）的小鼠长期存活，特别是与靶向抗血管生成药物联合使用时。然而，与MTD类似，化疗最终会产生获得性耐药，其基础尚不清楚。通过在SCID小鼠中建立晚期人卵巢癌（SKOV-3-13）临床前模型，我们发现，在每日口服节律性拓扑替康加口服抗血管生成酪氨酸激酶抑制剂（TKI）帕唑帕尼（pazopanib）的长期（超过3个月）成功治疗结束后，获得性耐药可能会发生。从一只小鼠中分离出两种耐药亚型，一种来自实体瘤（称为KH092-7SD，简称7SD），另一种来自腹水肿瘤细胞（称为KH092-7AS，简称7AS）。通过这些亚组，我们发现对联合治疗的获得性耐药是由于肿瘤细胞的改变，赋予拓扑替康相对难治性。耐药表型是可遗传的，与拓扑替康的细胞摄取减少有关，并且不能通过切换到MTD拓扑替康或另一种拓扑异构酶-1抑制剂CPT-11（以节拍或MTD方式给予）或切换到另一种抗血管生成药物（例如抗VEGFR-2抗体DC101或另一种TKI舒尼替尼）来逆转。因此，在这种情况下，MTD和节拍拓扑替康之间似乎存在交叉抗性，其基础尚不清楚。然而，基因表达谱揭示了在耐药系中稳定上调的几个潜在基因，这些基因先前与各种化疗药物的耐药有关，因此可能有助于耐药表型。
An alternative or follow-up adjunct to conventional maximum tolerated dose (MTD) chemotherapy now in advanced phase III clinical trial assessment is metronomic chemotherapy—the close regular administration of low doses of drug with no prolonged breaks. A number of preclinical studies have shown metronomic chemotherapy can cause long term survival of mice with advanced cancer, including metastatic disease, in the absence of overt toxicity, especially when combined with targeted antiangiogenic drugs. However, similar to MTD chemotherapy acquired resistance eventually develops, the basis of which is unknown. Using a preclinical model of advanced human ovarian (SKOV-3-13) cancer in SCID mice, we show that acquired resistance can develop after terminating prolonged (over 3 months) successful therapy utilizing daily oral metronomic topotecan plus pazopanib, an oral antiangiogenic tyrosine kinase inhibitor (TKI). Two resistant sublines were isolated from a single mouse, one from a solid tumor (called KH092-7SD, referred to as 7SD) and another from ascites tumor cells (called KH092-7AS, referred to as 7AS). Using these sublines we show acquired resistance to the combination treatment is due to tumor cell alterations that confer relative refractoriness to topotecan. The resistant phenotype is heritable, associated with reduced cellular uptake of topotecan and could not be reversed by switching to MTD topotecan or to another topoisomerase-1 inhibitor, CPT-11, given either in a metronomic or MTD manner nor switching to another antiangiogenic drug, e.g. the anti- VEGFR-2 antibody, DC101, or another TKI, sunitinib. Thus, in this case cross resistance seems to exist between MTD and metronomic topotecan, the basis of which is unknown. However, gene expression profiling revealed several potential genes that are stably upregulated in the resistant lines, that previously have been implicated in resistance to various chemotherapy drugs, and which, therefore, may contribute to the drug resistant phenotype.