Synergy between methionine stress and chemotherapy in the treatment of brain tumor xenografts in athymic mice.
Synergy between methionine stress and chemotherapy in the treatment of brain tumor xenografts in athymic mice.
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发表时间：
2001-05
期刊：
影响因子：
11.2
通讯作者：
D. Kokkinakis;Robert M. Hoffman;Eugene P. Frenkel;Jacquelynn B. Wick;Qinghong Han;Mingxu Xu;Yuying Tan;S. Schold
中科院分区：
文献类型：
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作者：
D. Kokkinakis;Robert M. Hoffman;Eugene P. Frenkel;Jacquelynn B. Wick;Qinghong Han;Mingxu Xu;Yuying Tan;S. Schold
本研究描述了一种结合重组l -蛋氨酸- α -脱氨基- γ -裂解酶和目前用于治疗此类肿瘤的化疗方案治疗脑肿瘤的新方法。在不含蛋氨酸和胆碱的饮食和重组l -蛋氨酸-脱氨基- γ -裂解酶联合消耗小鼠血浆蛋氨酸（MET）后，day、SWB77和D-54异种移植物在胸腺小鼠体内的生长被阻止。用每日i.p.同型半胱氨酸治疗的荷瘤小鼠从MET停药的毒性作用中获救。该方案将血浆MET水平抑制至5微米以下数天，无治疗相关死亡。10-12天的MET耗竭诱导肿瘤有丝分裂和细胞周期阻滞、凋亡性死亡和广泛坏死，但在停止治疗后不能阻止肿瘤再生。然而，当在MET消耗方案结束时给予单剂量35mg /m(2)的N，N'-双（2-氯乙基）-N-亚硝基脲（BCNU）时，观察到day和D-54的生长延迟超过80天，而SWB77的生长延迟20天。当在10天的MET消耗期结束时，给动物以180 mg/m(2)的单剂量替莫唑胺（TMZ）给药时，替莫唑胺（TMZ）对SWB77的疗效也增加了两倍。稻和SWB77对BCNU和TMZ等DNA烷基化剂的反应增强可能与下调O(6)-甲基鸟嘌呤-DNA甲基转移酶活性有关。然而，在不表达可测量的O(6)-甲基鸟嘌呤- dna甲基转移酶蛋白的D-54肿瘤中观察到MET消耗和BCNU的协同作用，可能是由不同的机制介导的。MET耗损特异性地使肿瘤对烷基化剂敏感，并不能显著降低BCNU或TMZ对宿主的毒性。在这方面，MET消耗和基因毒性化疗的联合方法在临床评估中具有重要的前景。
This study describes a novel approach to the treatment of brain tumors with the combination of recombinant L-methionine-alpha-deamino-gamma-lyase and chemotherapeutic regimens that are currently used against such tumors. The growth of Daoy, SWB77, and D-54 xenografts in athymic mice was arrested after the depletion of mouse plasma methionine (MET) with a combination of a MET- and choline-free diet and recombinant L-methionine-alpha-deamino-gamma-lyase. The treated tumor-bearing mice were rescued from the toxic effects of MET withdrawal with daily i.p. homocystine. This regimen suppressed plasma MET to levels below 5 microM for several days, with no treatment-related deaths. MET depletion for 10-12 days induced mitotic and cell cycle arrest, apoptotic death, and widespread necrosis in tumors but did not prevent tumor regrowth after cessation of the regimen. However, when a single dose of 35 mg/m(2) of N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU), which was otherwise ineffective as a single therapy in any of the tumors tested, was given at the end of the MET depletion regimen, a more than 80-day growth delay was observed for Daoy and D-54, whereas the growth of SWB77 was delayed by 20 days. MET-depleting regimens also trebled the efficacy of temozolomide (TMZ) against SWB77 when TMZ was given to animals as a single dose of 180 mg/m(2) at the end of a 10-day period of MET depletion. The enhanced responses of both Daoy and SWB77 to DNA alkylating agents such as BCNU and TMZ could be attributed to the down-regulation of O(6)-methylguanine-DNA methyltransferase activity. However, the synergy of MET depletion and BCNU observed with D-54 tumors, which do not express measurable O(6)-methylguanine-DNA methyltransferase protein, is probably mediated by a different mechanism. MET depletion specifically sensitizes tumors to alkylating agents and does not significantly lower the toxicity of either BCNU or TMZ for the host. In this regard, the combination approach of MET depletion and genotoxic chemotherapy demonstrates significant promise for clinical evaluation.