Grem J L, van Groeningen C J, Ismail A A, Johnston P G, Alexander H R, Allegra C J
NCI-NMOB, National Naval Medical Center, Bethesda, Maryland 20889-5105, USA.
Eur J Cancer. 1995 Jul-Aug;31A(7-8):1316-20. doi: 10.1016/0959-8049(95)91267-g.
Several preclinical studies have demonstrated that interferon-alpha (IFN-alpha) may enhance the cytotoxicity of fluoropyrimidines in a greater-than-additive manner in a variety of human cancer cell lines. The underlying mechanism(s) have varied in different cancer cell lines, and include increased fluorouracil anabolism to fluorodeoxyuridine monophosphate, further inhibition of thymidylate synthase, stimulation of thymidine and uridine phosphorylase activities, greater DNA damage, and enhanced natural killer cell-mediated lysis of tumour targets. These preclinical studies stimulated clinical evaluation of IFN-alpha in combination with 5-fluorouracil (5-FU) with and without leucovorin (LV), and the initial clinical results appeared promising. We summarise preclinical research concerning the interaction of 5-FU and IFN-alpha. The rationale for combining 5-FU with IFN-alpha and LV is discussed, and we describe our clinical experience with the combination of 5-FU, LV and IFN-alpha-2a. The insights and unresolved questions concerning the clinical application of this combination are also discussed.
多项临床前研究表明，在多种人类癌细胞系中，α干扰素（IFN-α）可能以大于相加的方式增强氟嘧啶的细胞毒性。其潜在机制在不同癌细胞系中有所不同，包括氟尿嘧啶合成氟脱氧尿苷单磷酸的代谢增强、胸苷酸合成酶的进一步抑制、胸苷和尿苷磷酸化酶活性的刺激、更大程度的DNA损伤以及自然杀伤细胞介导的肿瘤靶细胞裂解增强。这些临床前研究促使人们对IFN-α与5-氟尿嘧啶（5-FU）联合使用（加或不加亚叶酸（LV））进行临床评估，初步临床结果似乎很有前景。我们总结了关于5-FU与IFN-α相互作用的临床前研究。讨论了5-FU与IFN-α和LV联合使用的原理，并描述了我们使用5-FU、LV和IFN-α-2a联合治疗的临床经验。还讨论了关于这种联合治疗临床应用的见解和未解决的问题。
