THE INVITRO AND INVIVO ANTI-RETROVIRUS ACTIVITY, AND INTRACELLULAR METABOLISM OF 3'-AZIDO-2',3'-DIDEOXYTHYMIDINE AND 2',3'-DIDEOXYCYTIDINE ARE HIGHLY DEPENDENT ON THE CELL SPECIES
THE INVITRO AND INVIVO ANTI-RETROVIRUS ACTIVITY, AND INTRACELLULAR METABOLISM OF 3'-AZIDO-2',3'-DIDEOXYTHYMIDINE AND 2',3'-DIDEOXYCYTIDINE ARE HIGHLY DEPENDENT ON THE CELL SPECIES
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DOI：
10.1016/0006-2952(88)90178-5
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发表时间：
1988-03-01
影响因子：
5.8
通讯作者：
JOHNS, DG
中科院分区：
文献类型：
--
作者：
BALZARINI, J;PAUWELS, R;JOHNS, DG
来自不同物种的细胞株对3‘’-叠氮-2‘，3’‘-二脱氧胸苷(AzddThd)和2’‘，3’‘-双脱氧胞苷(DdCyd)的细胞抑制和抗逆转录病毒活性以及细胞内代谢的敏感性存在显著差异。AzddThd和ddCyd对人(即Raji、Molt/4F、ATH8)细胞系的细胞抑制作用明显强于小鼠(即L1210)细胞。细胞内形成的AzddThd 5‘’-三磷酸和ddCyd 5‘’-三磷酸的水平似乎与这些化合物所达到的细胞抑制作用无关。在人淋巴样细胞(ATH8，Molt/4F)和山羊卵巢(Tahr)细胞中，AzddThd以5‘-单磷酸(AzddTMP)的形式蓄积，而在小鼠白血病(L1210)细胞中，AzddThd很容易被代谢成5’‘-三磷酸(AzddTTP)。AzddThd在小鼠细胞中快速转化为AzddTTP，这可能解释了AzddThd在体外对Moloney小鼠肉瘤病毒(MSV)诱导的小鼠C3H细胞转化和MSV诱导的新生NMRI小鼠体内肿瘤形成具有明显的抑制作用。相比之下，ddCyd在这些小鼠检测系统中没有太多活性，这可能与小鼠细胞中ddCyd转化为5‘’-三磷酸的能力较差有关。然而，在人类细胞中，ddCyd比在小鼠细胞中更广泛地被磷酸化为其5‘’-三磷酸。比较[~3H]AzddThd和[~3H]ddCyd在ATH8和Molt/4F细胞中的代谢，即使在孵育48小时后也几乎没有形成[~3H]AzddTTP，而在相同条件下，[~3H]ddCTP逐渐增加。因此，在人类淋巴样细胞中，ddCTP水平比AzddTTP水平高得多，从治疗的角度来看，这一观察结果可能特别相关。
Cell lines derived from different species show striking differences in their sensitivity to the cytostatic and anti-retrovirus activity, as well as the intracellular metabolism, of 3''-azido-2'',3''-dideoxythymidine (AzddThd) and 2'',3''-dideoxycytidine (ddCyd). AzddThd and ddCyd are considerably more cytostatic to human (i.e. Raji, Molt/4F, ATH8) cell lines than murine (i.e. L1210) cells. The intracellular levels of AzddThd 5''-triphosphate and ddCyd 5''-triphosphate formed do not seem related to the cytostatic effects achieved by these compounds. In human lymphoid (ATH8, Molt/4F) and caprine ovary (Tahr) cells AzddThd accumulates as its 5''-monophosphate (AzddTMP), whereas in murine leukemia (L1210) cells it is readily metabolized to the 5''-triphosphate (AzddTTP). The rapid conversion of AzddThd to AzddTTP in murine cells may explain why AzddThd has a pronounced activity againt Moloney murine sarcoma virus (MSV)-induced transformation of murine C3H cells in vitro and MSV-induced tumor development in newborn NMRI mice in vivo. In contrast, ddCyd has not much activity in these murine assay systems, and this may seem related to the poor conversion of ddCyd to its 5''-triphosphate in murine cells. In human cells, however, ddCyd is more extensively phosphorylated to its 5''-triphosphate than in murine cells. When [3H]AzddThd and [3H]ddCyd were compared for their metabolism in ATH8 and Molt/4F cells, little [3H]AzddTTP was formed even after a 48-hr incubation period, whereas under the same conditions substantial levels of [3H]ddCTP built up gradually. Thus, much higher ddCTP than AzddTTP levels were achieved in human lymphoid cells, an observation that may be particularly relevant from a therapeutic viewpoint.