Sipos E P, Witham T F, Ratan R, Burger P C, Baraban J, Li K W, Piantadosi S, Brem H
Department of Neurological Surgery, Johns Hopkins Hospital and School of Medicine, Baltimore, Maryland, USA.
Neurosurgery. 2001 Feb;48(2):392-400. doi: 10.1097/00006123-200102000-00032.
L-buthionine sulfoximine (BSO) inhibits glutathione synthesis and may modulate tumor resistance to some alkylating agents, but it has not been proven effective in the treatment of intracranial neoplasms. To evaluate this drug for the treatment of brain tumors, we studied the use of BSO for potentiating the antineoplastic effect of 4-hydroxyperoxycyclophosphamide (4-HC) in the rat 9L glioma model.
The survival of male Fischer 344 rats with intracranial 9L gliomas was measured after implantation of controlled-release polymers containing one of the following: no drug, BSO, 4-HC, or both BSO and 4-HC. The efficacy of intracranial 4-HC treatment was assessed with and without serial systemic intraperitoneal BSO injections. Tissue glutathione levels were measured in the brains, tumors, and livers of animals treated with intraperitoneal injections or local delivery of BSO.
The median survival of animals treated with intracranial polymers containing 4-HC was 2.3 times greater than that of controls. This survival benefit was doubled by local delivery of BSO. In contrast, systemic BSO therapy did not improve survival time. In animals that were treated systemically, both liver and tumor glutathione levels were significantly lower than they were in control animals. In the locally treated animals, glutathione levels were reduced in the brain tumor but not in the liver.
These results demonstrate that local but not systemic delivery of BSO enhances the antineoplastic effect of 4-HC in this rat 9L glioma model. In addition, because local delivery of BSO within the brain did not deplete glutathione levels systemically, this method of treatment may be safer than systemic administration of BSO.
L-丁硫氨酸亚砜胺（BSO）可抑制谷胱甘肽合成，并可能调节肿瘤对某些烷化剂的耐药性，但尚未证实其对颅内肿瘤治疗有效。为评估该药对脑肿瘤的治疗效果，我们研究了在大鼠9L胶质瘤模型中使用BSO增强4-羟基过氧环磷酰胺（4-HC）的抗肿瘤作用。
将含有以下物质之一的控释聚合物植入雄性Fischer 344大鼠颅内9L胶质瘤后，测量其存活情况：无药物、BSO、4-HC或BSO与4-HC两者。在有或无连续全身腹腔注射BSO的情况下，评估颅内4-HC治疗的疗效。对经腹腔注射或局部给予BSO治疗的动物的脑、肿瘤和肝脏组织中的谷胱甘肽水平进行测量。
用含4-HC的颅内聚合物治疗的动物的中位生存期比对照组高2.3倍。局部给予BSO使这种生存获益增加了一倍。相比之下，全身BSO治疗并未改善生存时间。在接受全身治疗的动物中，肝脏和肿瘤中的谷胱甘肽水平均显著低于对照动物。在局部治疗的动物中，脑肿瘤中的谷胱甘肽水平降低，但肝脏中未降低。
这些结果表明，在该大鼠9L胶质瘤模型中，局部而非全身给予BSO可增强4-HC的抗肿瘤作用。此外，由于在脑内局部给予BSO不会使全身谷胱甘肽水平降低，这种治疗方法可能比全身给予BSO更安全。
