Rodriguez-Vicente J, Vicente-Ortega V, Canteras-Jordana M
Department of Pathology, Faculty of Medicine, University of Murcia, Spain.
Cancer. 1998 Feb 1;82(3):495-502. doi: 10.1002/(sici)1097-0142(19980201)82:3<495::aid-cncr11>3.0.co;2-x.
The chemotherapy of melanoma patients must be improved because of the naturally poor response and acquired resistance of this disease.
The authors used mouse (B16F10) and human (SK-MEL-28 and SK-MEL-1) melanoma lines for in vitro treatment with melphalan, lomustine, fotemustine, and 4-hydroxyanisole (4-HA) alone, combined and after pretreatment with buthionine sulfoximine (BSO), ethacrynic acid (EA), and azelaic acid (AZA).
Melphalan was the most effective individual drug, followed by lomustine, fotemustine, and 4-HA. The simultaneous administration of two agents was disappointing, although some combinations slightly improved the response compared with the individual treatments. Pretreatment with BSO enhanced the cytotoxicity of melphalan and lomustine 10-fold in B16F10 and 7.5-fold in SK-MEL-28, increasing the toxicity of fotemustine in all 3 lines. EA potentiated lomustine and fotemustine 9-fold and melphalan 5-fold in B16F10 and SK-MEL-28. AZA increased the effectiveness of lomustine and fotemustine in B16F10 and to a lower degree in the two human lines. 4-HA was the poorest drug for sensitization; only B16F10 BSO followed by 4-HA treatment demonstrated increased toxicity, and all other combinations with 4-HA were negative or antagonistic. There was a strong relationship between dopa oxidase activity and the toxicity of 4-HA.
B16F10 was the most sensitive to all treatments and SK-MEL-1 the most resistant. Melphalan was the most active individual drug and 4-HA the least. Combinations of two drugs did not result in improved activity compared with drugs administered alone. Pretreatment with modulator seems to be a potential method for enhancing some treatments.
由于黑色素瘤患者对治疗天生反应不佳且会产生获得性耐药，其化疗方案必须改进。
作者使用小鼠（B16F10）和人（SK-MEL-28及SK-MEL-1）黑色素瘤细胞系，分别用美法仑、洛莫司汀、福莫司汀和4-羟基茴香醚（4-HA）单独处理、联合处理，以及在使用丁硫氨酸亚砜胺（BSO）、依他尼酸（EA）和壬二酸（AZA）预处理后进行处理。
美法仑是最有效的单一药物，其次是洛莫司汀、福莫司汀和4-HA。同时使用两种药物的效果令人失望，尽管与单一药物治疗相比，一些联合用药略微改善了反应。用BSO预处理可使美法仑和洛莫司汀在B16F10中的细胞毒性增强10倍，在SK-MEL-28中增强7.5倍，并增加福莫司汀在所有三种细胞系中的毒性。EA在B16F10和SK-MEL-28中使洛莫司汀和福莫司汀的效力增强9倍，使美法仑增强5倍。AZA增加了洛莫司汀和福莫司汀在B16F10中的效力，在两个人类细胞系中的增强程度较低。4-HA是最不利于致敏的药物；只有先用B16F10 BSO再用4-HA处理显示出毒性增加，而所有其他与4-HA的联合用药均为阴性或具有拮抗作用。多巴氧化酶活性与4-HA的毒性之间存在很强的关系。
B16F10对所有治疗最敏感，SK-MEL-1最耐药。美法仑是最具活性的单一药物，4-HA活性最低。与单独给药相比，两种药物联合使用并未提高活性。用调节剂预处理似乎是增强某些治疗效果的一种潜在方法。
