Cruz-Muñoz William, Di Desidero Teresa, Man Shan, Xu Ping, Jaramillo Maria Luz, Hashimoto Kae, Collins Catherine, Banville Myriam, O'Connor-McCourt Maureen D, Kerbel Robert S
Biological Sciences Platform, S-217, Sunnybrook Research Institute, 2075 Bayview Ave., Toronto, ON, M4N 3M5, Canada.
Angiogenesis. 2014 Jul;17(3):661-73. doi: 10.1007/s10456-014-9422-9. Epub 2014 Feb 26.
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.
目前正处于晚期III期临床试验评估阶段的传统最大耐受剂量（MTD）化疗的替代或后续辅助治疗方法是节拍化疗——即定期密切给予低剂量药物且无长时间中断。多项临床前研究表明，节拍化疗可使患有晚期癌症（包括转移性疾病）的小鼠长期存活，且无明显毒性，尤其是与靶向抗血管生成药物联合使用时。然而，与MTD化疗类似，最终会产生获得性耐药，其机制尚不清楚。利用SCID小鼠中晚期人卵巢癌（SKOV-3-13）的临床前模型，我们发现，在使用每日口服节拍拓扑替康加帕唑帕尼（一种口服抗血管生成酪氨酸激酶抑制剂（TKI））进行长期（超过3个月）成功治疗后，可产生获得性耐药。从一只小鼠中分离出两个耐药亚系，一个来自实体瘤（称为KH092-7SD，简称7SD），另一个来自腹水肿瘤细胞（称为KH092-7AS，简称7AS）。利用这些亚系，我们发现对联合治疗的获得性耐药是由于肿瘤细胞发生改变，从而使细胞对拓扑替康产生相对难治性。耐药表型具有遗传性，与拓扑替康的细胞摄取减少有关，并不能通过改用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方式给药）或改用另一种抗血管生成药物（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耐药，其机制尚不清楚。然而，基因表达谱分析揭示了几个在耐药系中稳定上调的潜在基因，这些基因以前与对各种化疗药物的耐药性有关，因此可能导致耐药表型。
