Skapek S X, Colvin O M, Griffith O W, Elion G B, Bigner D D, Friedman H S
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710.
Cancer Res. 1988 May 15;48(10):2764-7.
The effect and therapeutic consequences of buthionine-(SR)-sulfoximine (BSO)-mediated depletion of glutathione in the human medulloblastoma-derived cell line, TE-671, growing as s.c. xenografts in athymic nude mice were examined. The glutathione content of the s.c. xenografts was 1.11 +/- 0.15 mumol/g (7.79 +/- 1.61 nmol/mg of protein). Administration i.p. to tumor-bearing mice of D,L-BSO (two doses at 12-h intervals; 5 mmol/kg) depleted the glutathione content of the xenografts to 25.7% of control. Administration of a 30 mM solution of L-BSO in drinking water for 96 h depleted the glutathione content to 17.4% of control. Depletion of glutathione with these regimens resulted in a significant increase in the s.c. tumor growth delay over that produced by melphalan alone: 17.2 days versus 12.6 days for D,L-BSO (i.p.) plus melphalan versus melphalan and 22.9 days versus 16.6 days for L-BSO (p.o.) plus melphalan versus melphalan. These studies demonstrate the increased cytotoxicity of melphalan resulting from BSO-mediated depletion of glutathione in human medulloblastoma and support further efforts to modulate the chemosensitivity and radiosensitivity of this tumor by modulation of glutathione.
研究了丁硫氨酸 -（SR）- 亚砜胺（BSO）介导的谷胱甘肽耗竭对人髓母细胞瘤衍生细胞系TE - 671的影响及其治疗后果，该细胞系在无胸腺裸鼠体内以皮下异种移植物的形式生长。皮下异种移植物的谷胱甘肽含量为1.11±0.15μmol/g（7.79±1.61nmol/mg蛋白质）。对荷瘤小鼠腹腔注射D，L - BSO（间隔12小时注射两剂；5mmol/kg）可使异种移植物的谷胱甘肽含量降至对照的25.7%。在饮用水中给予30mM的L - BSO溶液96小时可使谷胱甘肽含量降至对照的17.4%。与单独使用美法仑相比，这些方案导致的谷胱甘肽耗竭使皮下肿瘤生长延迟显著增加：D，L - BSO（腹腔注射）加美法仑为17.2天，而美法仑单独使用为12.6天；L - BSO（口服）加美法仑为22.9天，而美法仑单独使用为16.6天。这些研究证明了在人髓母细胞瘤中，BSO介导的谷胱甘肽耗竭导致美法仑的细胞毒性增加，并支持通过调节谷胱甘肽来进一步调节该肿瘤的化学敏感性和放射敏感性的努力。
