Hargrove J L, Granner D K
J Cell Physiol. 1982 Jun;111(3):232-8. doi: 10.1002/jcp.1041110303.
The following evidence suggests that inhibition of hepatoma cell (HTC) growth by cyclic nucleotides is an adenosine-like effect that is greatly modified by the type and treatment of serum used in the culture medium and is probably not mediated by cyclic AMP-dependent protein kinase: 1) Heating serum reduces its phosphodiesterase content, thereby slowing metabolism of cyclic AMP and reducing the inhibition of HTC cell growth by cyclic AMP; 2) Using medium that contains phosphodiesterase but lacks adenosine deaminase causes adenosine to accumulate from cyclic AMP and increases the toxicity of cyclic AMP; 3) Uridine or cytidine reverses the growth inhibition caused by adenosine, 5'-AMP or cyclic AMP; 4) adenosine, 5'-AMP and N6-(delta 2-isopentenyl) adenosine are more toxic for HTC cells than is cyclic AMP, and N6,O2-dibutyryl cyclic AMP is not toxic; and 5) N6,O2'-dibutyryl cyclic AMP inhibits growth of Reuber H35 cells, but uridine prevents this inhibition of growth. We conclude that most, if not all, of the inhibitory effects of cyclic AMP and N6,O2'-dibutyryl cyclic AMP on HTc and Reuber H35 hepatoma cell growth are due to the generation of toxic metabolites.
以下证据表明，环核苷酸对肝癌细胞（HTC）生长的抑制是一种类似腺苷的效应，这种效应会因培养基中所用血清的类型和处理方式而发生很大改变，并且可能不是由环磷酸腺苷依赖性蛋白激酶介导的：1）加热血清会降低其磷酸二酯酶含量，从而减缓环磷酸腺苷的代谢，并降低环磷酸腺苷对HTC细胞生长的抑制作用；2）使用含有磷酸二酯酶但缺乏腺苷脱氨酶的培养基会使腺苷从环磷酸腺苷中积累，并增加环磷酸腺苷的毒性；3）尿苷或胞苷可逆转由腺苷、5'-腺苷酸或环磷酸腺苷引起的生长抑制；4）腺苷、5'-腺苷酸和N6-（δ2-异戊烯基）腺苷对HTC细胞的毒性比环磷酸腺苷更大，而N6,O2-二丁酰环磷酸腺苷无毒；5）N6,O2'-二丁酰环磷酸腺苷可抑制鲁伯H35细胞的生长，但尿苷可阻止这种生长抑制。我们得出结论，环磷酸腺苷和N6,O2'-二丁酰环磷酸腺苷对HTC和鲁伯H35肝癌细胞生长的大部分（如果不是全部）抑制作用是由于有毒代谢产物的产生。
