PDF(Pubmed)
Abstract：
BACKGROUND: We previously reported that metastases are generally characterized by a core program of gene expression that activates tissue remodeling/vascularization, alters ion homeostasis, induces the oxidative metabolism, and silences extracellular matrix interactions. This core program distinguishes metastases from their originating primary tumors as well as from their destination host tissues. Therefore, the gene products involved are potential targets for anti-metastasis drug treatment.
METHODS: Because the silencing of extracellular matrix interactions predisposes to anoiks in the absence of active survival mechanisms, we tested inhibitors against the other three components.
RESULTS: Individually, the low-specificity VEGFR blocker pazopanib (in vivo combined with marimastat), the antioxidant dimethyl sulfoxide (or the substitute atovaquone, which is approved for internal administration), and the ionic modulators bumetanide and tetrathiomolybdate inhibited soft agar colony formation by breast and pancreatic cancer cell lines. The individual candidate agents have a record of use in humans (with limited efficacy when administered individually) and are available for repurposing. In combination, the effects of these drugs were additive or synergistic. In two mouse models of cancer (utilizing 4T1 cells or B16-F10 cells), the combination treatment with these medications, applied immediately (to prevent metastasis formation) or after a delay (to suppress established metastases), dramatically reduced the occurrence of disseminated foci.
CONCLUSIONS: The combination of tissue remodeling inhibitors, suppressors of the oxidative metabolism, and ion homeostasis modulators has very strong promise for the treatment of metastases by multiple cancers.
METHODS: Because the silencing of extracellular matrix interactions predisposes to anoiks in the absence of active survival mechanisms, we tested inhibitors against the other three components.
RESULTS: Individually, the low-specificity VEGFR blocker pazopanib (in vivo combined with marimastat), the antioxidant dimethyl sulfoxide (or the substitute atovaquone, which is approved for internal administration), and the ionic modulators bumetanide and tetrathiomolybdate inhibited soft agar colony formation by breast and pancreatic cancer cell lines. The individual candidate agents have a record of use in humans (with limited efficacy when administered individually) and are available for repurposing. In combination, the effects of these drugs were additive or synergistic. In two mouse models of cancer (utilizing 4T1 cells or B16-F10 cells), the combination treatment with these medications, applied immediately (to prevent metastasis formation) or after a delay (to suppress established metastases), dramatically reduced the occurrence of disseminated foci.
CONCLUSIONS: The combination of tissue remodeling inhibitors, suppressors of the oxidative metabolism, and ion homeostasis modulators has very strong promise for the treatment of metastases by multiple cancers.
摘要：
背景：我们以前报道，转移通常以激活组织重塑/血管形成的基因表达的核心程序为特征，改变离子稳态，诱导氧化代谢，并沉默细胞外基质相互作用。该核心程序将转移与它们的起源原发性肿瘤以及它们的目的地宿主组织区分开来。因此,所涉及的基因产物是抗转移药物治疗的潜在靶点.
方法：因为细胞外基质相互作用的沉默在没有主动生存机制的情况下容易导致anoiks，我们测试了其他三种成分的抑制剂。
结果：个别地，低特异性VEGFR阻断剂帕唑帕尼（体内联合marimastat），抗氧化剂二甲基亚砜(或替代品阿托瓦醌，经批准用于内部管理)，离子调节剂布美他尼和四硫钼酸盐抑制乳腺癌和胰腺癌细胞系的软琼脂集落形成。个体候选药剂具有在人类中使用的记录(当单独施用时具有有限的功效)并且可用于再利用。在组合中，这些药物的作用是累加的或协同的。在两种小鼠癌症模型中（利用4T1细胞或B16-F10细胞），这些药物的联合治疗，立即应用（以防止转移形成）或延迟后（以抑制已建立的转移），大大减少了播散性病灶的发生。
结论：组织重塑抑制剂的组合，氧化代谢的抑制剂，和离子稳态调节剂对于治疗多种癌症的转移具有很强的前景。
方法：因为细胞外基质相互作用的沉默在没有主动生存机制的情况下容易导致anoiks，我们测试了其他三种成分的抑制剂。
结果：个别地，低特异性VEGFR阻断剂帕唑帕尼（体内联合marimastat），抗氧化剂二甲基亚砜(或替代品阿托瓦醌，经批准用于内部管理)，离子调节剂布美他尼和四硫钼酸盐抑制乳腺癌和胰腺癌细胞系的软琼脂集落形成。个体候选药剂具有在人类中使用的记录(当单独施用时具有有限的功效)并且可用于再利用。在组合中，这些药物的作用是累加的或协同的。在两种小鼠癌症模型中（利用4T1细胞或B16-F10细胞），这些药物的联合治疗，立即应用（以防止转移形成）或延迟后（以抑制已建立的转移），大大减少了播散性病灶的发生。
结论：组织重塑抑制剂的组合，氧化代谢的抑制剂，和离子稳态调节剂对于治疗多种癌症的转移具有很强的前景。
