Comparison of the Lonidamine Potentiated Effect of Nitrogen Mustard Alkylating Agents on the Systemic Treatment of DB-1 Human Melanoma Xenografts in Mice.
Comparison of the Lonidamine Potentiated Effect of Nitrogen Mustard Alkylating Agents on the Systemic Treatment of DB-1 Human Melanoma Xenografts in Mice.
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DOI：
10.1371/journal.pone.0157125
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Glickson JD
中科院分区：
文献类型：
--
作者：
Nath K;Nelson DS;Putt ME;Leeper DB;Garman B;Nathanson KL;Glickson JD
先前的核磁共振研究表明，lonidamine （LND）选择性地降低DB-1黑色素瘤和多种其他常见人类癌症的小鼠异种移植物的细胞内pH (pHi)，同时降低它们的生物能量状态（肿瘤βNTP/Pi比率），并增强这些癌症模型中melphalan和阿霉素的活性。由于美法兰和阿霉素是剧毒剂，我们检测了另外三种氮(N)-芥菜，氯苯，环磷酰胺和苯达莫司汀，以确定它们是否表现出类似的LND增强作用。作为单一药物LND， melphalan和这些n -mustard在DB-1黑色素瘤异种移植中表现出以下活性：LND: 100%肿瘤存活率（SF）；氯苯：100% SF；环磷酰胺：100% SF；苯达莫司汀：79% SF；梅尔法兰：41% SF。当在n -芥菜处理前40分钟与LND联合使用（以最大限度地提高细胞内酸化）时，获得了以下反应；氯苯：62% SF；环磷酰胺：42% SF；苯达莫司汀：36% SF；melphalan: 10% SF。LND对这些n -芥菜活性的影响通常归因于酸稳定aziridinium活性中间体，酸抑制谷胱甘肽- s -转移酶（作为aziridinium的清除剂），以及酸抑制o6 -烷基转移酶的DNA修复。LND耗竭ATP也可能降低多药耐药，增加肿瘤反应。在相似的最大耐受剂量下，我们的数据表明，在治疗小鼠DB-1黑色素瘤时，美法兰是n -芥菜与LND联合治疗最有效的药物，但选择n -芥菜与LND共给药也取决于这些药物的相对毒性，并且仍有待确定。
Previous NMR studies demonstrated that lonidamine (LND) selectively diminishes the intracellular pH (pHi) of DB-1 melanoma and mouse xenografts of a variety of other prevalent human cancers while decreasing their bioenergetic status (tumor βNTP/Pi ratio) and enhancing the activities of melphalan and doxorubicin in these cancer models. Since melphalan and doxorubicin are highly toxic agents, we have examined three other nitrogen (N)-mustards, chlorambucil, cyclophosphamide and bendamustine, to determine if they exhibit similar potentiation by LND. As single agents LND, melphalan and these N-mustards exhibited the following activities in DB-1 melanoma xenografts; LND: 100% tumor surviving fraction (SF); chlorambucil: 100% SF; cyclophosphamide: 100% SF; bendamustine: 79% SF; melphalan: 41% SF. When combined with LND administered 40 min prior to administration of the N-mustard (to maximize intracellular acidification) the following responses were obtained; chlorambucil: 62% SF; cyclophosphamide: 42% SF; bendamustine: 36% SF; melphalan: 10% SF. The effect of LND on the activities of these N-mustards is generally attributed to acid stabilization of the aziridinium active intermediate, acid inhibition of glutathione-S-transferase, which acts as a scavenger of aziridinium, and acid inhibition of DNA repair by O6-alkyltransferase. Depletion of ATP by LND may also decrease multidrug resistance and increase tumor response. At similar maximum tolerated doses, our data indicate that melphalan is the most effective N-mustard in combination with LND when treating DB-1 melanoma in mice, but the choice of N-mustard for coadministration with LND will also depend on the relative toxicities of these agents, and remains to be determined.