Miwa M, Eda H, Ura M, Ouchi K F, Keith D D, Foley L H, Ishitsuka H
Nippon Roche Research Center, Kanagawa, Japan.
Clin Cancer Res. 1998 Feb;4(2):493-7.
2'-Deoxy-2'-methylidenecytidine (DMDC) is a new 2'-deoxycytidine (dCyd) antimetabolite. The present study compared its antitumor activities with those of 2',2'-difluorodeoxy-cytidine (gemcitabine) in 15 human cancer xenograft models. DMDC was highly resistant to cytidine (Cyd) deaminase, which deaminates the dCyd analogues to inactive molecules, whereas gemcitabine was susceptible to the enzyme. Given p.o., high antitumor activity with therapeutic index of more than 10 was found with DMDC in 7 of 15 xenograft lines. In contrast, gemcitabine given i.v. or p.o. was highly effective in 4 of 15 human cancer xenograft lines. The antitumor spectrum of these compounds was quite different, although their molecular targets are reported to be similar. DMDC was highly effective in tumors with higher levels of Cyd deaminase activity, whereas it showed only slight activity in those with lower levels of Cyd deaminase. In contrast, gemcitabine appeared to be less effective in tumors with high levels of Cyd deaminase. We also investigated the correlation with the susceptibility to the two dCyd antimetabolites and dCyd kinase activity in tumors, but none was observed. Cyd deaminase activity was found to be high in tumor tissues from various types of human cancers thus far tested, such as colorectal cancer and non-small cell lung cancer. Such cancer types or individual patients who have tumors with high activity of the enzyme may be targets for DMDC therapy.
2'-脱氧-2'-亚甲基胞苷（DMDC）是一种新型的2'-脱氧胞苷（dCyd）抗代谢物。本研究在15种人癌异种移植模型中比较了其与2',2'-二氟脱氧胞苷（吉西他滨）的抗肿瘤活性。DMDC对胞苷（Cyd）脱氨酶具有高度抗性，该酶可将dCyd类似物脱氨为无活性分子，而吉西他滨对该酶敏感。口服给药时，在15种异种移植系中的7种中发现DMDC具有高抗肿瘤活性，治疗指数超过10。相比之下，静脉注射或口服吉西他滨在15种人癌异种移植系中的4种中高度有效。尽管据报道这些化合物的分子靶点相似，但其抗肿瘤谱却大不相同。DMDC在具有较高Cyd脱氨酶活性水平的肿瘤中高度有效，而在Cyd脱氨酶水平较低的肿瘤中仅表现出轻微活性。相比之下，吉西他滨在Cyd脱氨酶水平高的肿瘤中似乎效果较差。我们还研究了与这两种dCyd抗代谢物敏感性和肿瘤中dCyd激酶活性的相关性，但未观察到相关性。迄今为止，在诸如结直肠癌和非小细胞肺癌等各种类型的人类癌症的肿瘤组织中发现Cyd脱氨酶活性很高。具有该酶高活性肿瘤的此类癌症类型或个体患者可能是DMDC治疗的靶点。
