Port J L, Hochwald S N, Wang H Y, Burt M E
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Ann Thorac Surg. 1995 Aug;60(2):239-43; discussion 244. doi: 10.1016/0003-4975(95)00362-o.
Although surgical resection remains the mainstay of treatment for metastatic pulmonary sarcoma, 5-year survival approaches only 25%. Chemotherapy has been limited by tumor resistance and systemic toxicity. We assessed the efficacy of L-buthionine-SR-sulfoximine, an inhibitor of glutathione synthesis, as a sensitizer for isolated lung perfusion.
In experiment 1, sarcoma-bearing rats (n = 20) received either buthionine sulfoximine via intraperitoneal injection or Hespan. After the last injection, tumor glutathione levels were measured. In experiment 2, rats (n = 60) were injected with sarcoma intravenously. On day 6, animals were pretreated with either buthionine sulfoximine or Hespan intraperitoneally. On day 7, rats underwent isolated lung perfusion (Hespan or doxorubicin) or intravenous therapy (Hespan or doxorubicin). On day 14, tumor nodules were counted.
Buthionine sulfoximine effectively depleted tumor glutathione. Animals treated with intravenous therapy had no response to therapy, whereas those animals treated with doxorubicin isolated lung perfusion alone had a limited response. Buthionine-sulfoximine pretreatment in combination with doxorubicin isolated lung perfusion led to a 13-fold reduction in tumor nodules and 5 complete responses.
Buthionine-sulfoximine pretreatment in combination with doxorubicin isolated lung perfusion is superior to intravenous doxorubicin and doxorubicin isolated lung perfusion alone for the treatment of metastatic pulmonary sarcoma.
尽管手术切除仍是转移性肺肉瘤的主要治疗方法，但5年生存率仅接近25%。化疗一直受到肿瘤耐药性和全身毒性的限制。我们评估了谷胱甘肽合成抑制剂L-丁硫氨酸-SR-亚砜亚胺作为离体肺灌注增敏剂的疗效。
在实验1中，荷肉瘤大鼠（n = 20）通过腹腔注射接受丁硫氨酸亚砜亚胺或贺斯。最后一次注射后，测量肿瘤谷胱甘肽水平。在实验2中，大鼠（n = 60）静脉注射肉瘤。在第6天，动物通过腹腔注射接受丁硫氨酸亚砜亚胺或贺斯预处理。在第7天，大鼠接受离体肺灌注（贺斯或多柔比星）或静脉治疗（贺斯或多柔比星）。在第14天，计数肿瘤结节。
丁硫氨酸亚砜亚胺有效消耗肿瘤谷胱甘肽。接受静脉治疗的动物对治疗无反应，而仅接受多柔比星离体肺灌注的动物反应有限。丁硫氨酸亚砜亚胺预处理联合多柔比星离体肺灌注导致肿瘤结节减少13倍，5例完全缓解。
丁硫氨酸亚砜亚胺预处理联合多柔比星离体肺灌注在治疗转移性肺肉瘤方面优于静脉注射多柔比星和单独的多柔比星离体肺灌注。
