目的:本研究描述了通过redoxcycle\'mitocans\'如醌/抗坏血酸联合药物治疗胶质母细胞瘤的药理学策略,基于其肿瘤选择性氧化还原调节作用和对正常细胞和组织的耐受性。方法:在用辅酶Q0/抗坏血酸(Q0/A)处理的胶质母细胞瘤小鼠(原位模型)上进行实验。该药以单剂量颅内注射。使用常规测定法使用MRIorex在体内分析以下参数:肿瘤生长,生存,脑和肿瘤灌注,肿瘤细胞密度,组织氧化还原状态,和肿瘤相关NADH氧化酶(tNOX)的表达。结果:Q0/A显著抑制胶质母细胞瘤小鼠的肿瘤生长并显著提高其存活率。这伴随着肿瘤中氧化应激的增加,而不是在非癌组织中,肿瘤血流量增加,和TNOX的下调。Q0/A的氧化还原调节和抗癌作用比我们先前研究中获得的甲萘醌/抗坏血酸(M/A)更明显。在用Q0/A治疗的胶质母细胞瘤小鼠中未观察到与药物相关的不良副作用。讨论:Q0/A分化的癌细胞和组织,特别是胶质母细胞瘤,从正常的氧化还原靶向,在肿瘤中引起严重的氧化应激,而不是在非癌组织中。Q0/A具有明显的抗癌活性,在一定的浓度范围内对生物体是安全的。结果表明,必须控制肿瘤吸收和有毒残留物代谢的速率,并将其维持在可耐受的范围内,以实现更长的生存期。尤其是颅内给药.
Objectives: The present
study describes a pharmacological strategy for the treatment of glioblastoma by redoxcycling \'mitocans\' such as quinone/ascorbate combination drugs, based on their tumor-selective redox-modulating effects and tolerance to normal cells and tissues.Methods: Experiments were performed on glioblastoma mice (orthotopic model) treated with coenzyme Q0/ascorbate (Q0/A). The drug was injected intracranially in a single dose. The following parameters were analyzed in vivo using MRI orex vivo using conventional assays: tumor growth, survival, cerebral and tumor perfusion, tumor cell density, tissue redox-state, and expression of tumor-associated NADH oxidase (tNOX).Results: Q0/A markedly suppressed tumor growth and significantly increased survival of glioblastoma mice. This was accompanied by increased oxidative stress in the tumor but not in non-cancerous tissues, increased tumor blood flow, and downregulation of tNOX. The redox-modulating and anticancer effects of Q0/A were more pronounced than those of
menadione/ascorbate (M/A) obtained in our previous
study. No adverse drug-related side-effects were observed in glioblastoma mice treated with Q0/A.Discussion: Q0/A differentiated cancer cells and tissues, particularly glioblastoma, from normal ones by redox targeting, causing a severe oxidative stress in the tumor but not in non-cancerous tissues. Q0/A had a pronounced anticancer activity and could be considered safe for the organism within certain concentration limits. The results suggest that the rate of tumor resorption and metabolism of toxic residues must be controlled and maintained within tolerable limits to achieve longer survival, especially at intracranial drug administration.