AntiCancer Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA; Division of Internal Medicine, Department of Medical Oncology, Showa University School of Medicine, Tokyo, Japan.
AntiCancer Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA.
Biochem Biophys Res Commun. 2024 Feb 5;695:149418. doi: 10.1016/j.bbrc.2023.149418. Epub 2023 Dec 25.
Glioma is a highly recalcitrant disease with a 5-year survival of 6.8 %. Temozolomide (TMZ), first-line therapy for glioma, is more effective in O-methylguanine-DNA methyltransferase (MGMT)-negative gliomas than in MGMT-positive gliomas as MGMT confers resistance to TMZ. Methionine restriction is effective for many cancers in mouse models including glioma. The concern is that methionine restriction could induce MGMT by decreasing DNA methylation and confer resistance to TMZ. In the present study, we investigated the efficacy of combining methionine restriction with TMZ for the treatment of MGMT-negative glioma, and whether methionine restriction induced MGMT. Human MGMT-negative U87 glioma cells were used to determine the efficacy of TMZ combined with methionine restriction. Recombinant methioninase (rMETase) inhibited U87 glioma growth without induction of MGMT in vitro. The combination of rMETase and TMZ inhibited U87 cell proliferation more than either agent alone in vitro. In the orthotopic nude-mouse model, the combination of TMZ and a methionine-deficient diet was much more effective than TMZ alone: two mice out of five were cured of glioma by the combination. No mice died during the treatment period. Methionine restriction enhanced the efficacy of TMZ in MGMT-negative glioma without inducing MGMT, demonstrating potential clinical promise for improved outcome of a currently incurable disease.
胶质母细胞瘤是一种高度难治的疾病，5 年生存率为 6.8%。替莫唑胺（TMZ）是胶质母细胞瘤的一线治疗药物，在 O-甲基鸟嘌呤-DNA 甲基转移酶（MGMT）阴性胶质母细胞瘤中比在 MGMT 阳性胶质母细胞瘤中更有效，因为 MGMT 赋予 TMZ 耐药性。蛋氨酸限制在包括胶质母细胞瘤在内的许多癌症的小鼠模型中是有效的。令人担忧的是，蛋氨酸限制通过降低 DNA 甲基化而诱导 MGMT，并赋予 TMZ 耐药性。在本研究中，我们研究了将蛋氨酸限制与 TMZ 联合用于治疗 MGMT 阴性胶质母细胞瘤的疗效，以及蛋氨酸限制是否诱导 MGMT。使用人 MGMT 阴性 U87 神经胶质瘤细胞来确定 TMZ 联合蛋氨酸限制的疗效。重组蛋氨酸酶（rMETase）在体外抑制 U87 神经胶质瘤的生长而不诱导 MGMT。rMETase 与 TMZ 的联合在体外比单独使用任何一种药物更能抑制 U87 细胞的增殖。在原位裸鼠模型中，TMZ 和蛋氨酸缺乏饮食的联合比 TMZ 单独使用更有效：五只小鼠中有两只被治愈。在治疗期间没有小鼠死亡。蛋氨酸限制增强了 TMZ 在 MGMT 阴性胶质母细胞瘤中的疗效，而没有诱导 MGMT，这表明在目前无法治愈的疾病中改善预后具有潜在的临床前景。
