Eda H, Ura M, F-Ouchi K, Tanaka Y, Miwa M, Ishitsuka H
Cytostatics Group, Nippon Roche Research Center, Kamakura, Kanagawa, Japan.
Cancer Res. 1998 Mar 15;58(6):1165-9.
We showed that the efficacy of the new 2'-deoxycytidine (2'-dCyd) analogue antimetabolite 2'-deoxy-2'-methylidenecytidine (DMDC) correlates well with tumor levels of cytidine (Cyd) deaminase in human cancer xenograft models. DMDC was highly effective in tumors with higher levels of Cyd deaminase, whereas lower levels yielded only slight activity. In contrast, gemcitabine (2',2'-difluorodeoxycytidine), which has action mechanisms similar to those of DMDC, is only slightly active in tumors with higher levels of the enzyme. In the present study, we investigated the roles of Cyd deaminase in the antitumor activity of the two 2'-dCyd antimetabolites in 13 human cancer cell lines. Tetrahydrouridine, an inhibitor of Cyd deaminase, reduced the antiproliferative activity of DMDC (P = 0.0015). Furthermore, tumor cells transfected with the gene of human Cyd deaminase become more susceptible to DMDC both in vitro and in vivo. These results indicate that Cyd deaminase is indeed essential for the activity of DMDC. In contrast, the antiproliferative activity of gemcitabine was increased to some extent by tetrahydrouridine (P = 0.0277), particularly in tumor cell lines with higher levels of Cyd deaminase. This suggests that higher levels of Cyd deaminase may inactivate gemcitabine. Among nucleosides and deoxynucleosides tested, only dCyd, a natural substrate of both Cyd deaminase and dCyd kinase, suppressed the antiproliferative activity of DMDC by up to 150-fold. Because the Vmax/Km of DMDC for dCyd kinase was 8-fold lower than that for dCyd, the activation of DMDC to DMDC monophosphate (DMDCMP) by dCyd kinase might be competitively inhibited by dCyd. In addition, the dCyd concentrations in human cancer xenografts were inversely correlated with levels of Cyd deaminase activity. It is therefore suggested that higher levels of Cyd deaminase reduce the intrinsic cellular concentrations of dCyd in tumors, resulting in efficient activation of DMDC to DMDCMP by dCyd kinase. These results indicate that the efficacy of DMDC may be predicted by measuring the activity of Cyd deaminase in tumor tissues before treatment starts and that DMDC may be exploited in a new treatment modality: tumor enzyme-driven cancer chemotherapy.
我们发现，新型2'-脱氧胞苷（2'-dCyd）类似物抗代谢物2'-脱氧-2'-亚甲基胞苷（DMDC）的疗效与人类癌症异种移植模型中胞苷（Cyd）脱氨酶的肿瘤水平密切相关。DMDC在Cyd脱氨酶水平较高的肿瘤中非常有效，而较低水平则仅产生轻微活性。相比之下，吉西他滨（2',2'-二氟脱氧胞苷）的作用机制与DMDC相似，在该酶水平较高的肿瘤中仅具有轻微活性。在本研究中，我们调查了Cyd脱氨酶在13种人类癌细胞系中这两种2'-dCyd抗代谢物的抗肿瘤活性中的作用。Cyd脱氨酶抑制剂四氢尿苷降低了DMDC的抗增殖活性（P = 0.0015）。此外，转染了人类Cyd脱氨酶基因的肿瘤细胞在体外和体内对DMDC均变得更敏感。这些结果表明，Cyd脱氨酶确实是DMDC活性所必需的。相比之下，四氢尿苷在一定程度上增加了吉西他滨的抗增殖活性（P = 0.0277），特别是在Cyd脱氨酶水平较高的肿瘤细胞系中。这表明较高水平的Cyd脱氨酶可能使吉西他滨失活。在所测试的核苷和脱氧核苷中，只有dCyd（Cyd脱氨酶和dCyd激酶的天然底物）将DMDC的抗增殖活性抑制了高达150倍。由于DMDC对dCyd激酶的Vmax/Km比对dCyd低8倍，dCyd激酶将DMDC激活为DMDC单磷酸酯（DMDCMP）的过程可能会被dCyd竞争性抑制。此外，人类癌症异种移植中的dCyd浓度与Cyd脱氨酶活性水平呈负相关。因此，有人提出较高水平的Cyd脱氨酶会降低肿瘤中dCyd的内在细胞浓度，从而导致dCyd激酶将DMDC有效激活为DMDCMP。这些结果表明，在治疗开始前通过测量肿瘤组织中Cyd脱氨酶的活性可以预测DMDC的疗效，并且DMDC可能会被用于一种新的治疗模式：肿瘤酶驱动的癌症化疗。
