Caffrey P B, Zhang Y, Frenkel G D
Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA.
Anticancer Res. 1998 Jul-Aug;18(4C):3021-5.
Human ovarian tumors from A2780 cells were grown as xenografts in immunodeficient mice, treated with a single i.p. dose of melphalan and tumor cells were removed and placed into tissue culture. The cells from the treated tumors exhibited an approximately 2-fold resistance to melphalan in vitro compared to cells taken from untreated tumors. This degree of resistance was similar to that of cells from tumors formed from melphalan-resistant A2780-ME cells. The cells from the treated tumors were also resistant to cisplatin but not to doxorubicin. They contained approximately 2-fold higher levels of glutathione than cells from the untreated tumors. Exposure of the cells to buthionine sulfoximine (a specific inhibitor of glutathione biosynthesis) eliminated the difference in glutathione levels as well as the difference in sensitivity to melphalan. When tumor-bearing animals were treated with buthionine sulfoximine in addition to melphalan the resulting tumor cells were not resistant to the drug. Resistance could also be demonstrated in the tumors themselves in vivo: the growth of previously untreated tumors was severely inhibited by a high dose of melphalan (11.7 mg/kg) administered i.p. to the animals, whereas the growth of tumors which had received prior treatment with melphalan was unaffected by the subsequent high dose. The rapid development of drug-resistant tumor cells after a single drug treatment in vivo makes this an excellent system for the investigation of the mechanisms by which resistance develops as well as for use in the screening for agents which can prevent it.
将来自A2780细胞的人卵巢肿瘤作为异种移植物在免疫缺陷小鼠中培养，用单剂量腹腔注射美法仑进行治疗，然后取出肿瘤细胞并置于组织培养中。与从未经治疗的肿瘤中取出的细胞相比，经治疗的肿瘤细胞在体外对美法仑表现出约2倍的抗性。这种抗性程度与来自耐美法仑的A2780-ME细胞形成的肿瘤中的细胞相似。经治疗的肿瘤细胞对顺铂也有抗性，但对阿霉素没有抗性。它们所含的谷胱甘肽水平比未经治疗的肿瘤中的细胞高出约2倍。将细胞暴露于丁硫氨酸亚砜胺（谷胱甘肽生物合成的特异性抑制剂）可消除谷胱甘肽水平的差异以及对美法仑敏感性的差异。当荷瘤动物除了接受美法仑治疗外还接受丁硫氨酸亚砜胺治疗时，产生的肿瘤细胞对该药物没有抗性。在体内肿瘤本身也可证明存在抗性：向动物腹腔注射高剂量美法仑（11.7 mg/kg）可严重抑制先前未经治疗的肿瘤的生长，而先前接受美法仑治疗的肿瘤的生长不受随后高剂量的影响。在体内单次药物治疗后耐药肿瘤细胞的快速产生，使其成为研究耐药性产生机制以及用于筛选可预防耐药性的药物的极佳系统。
