Saunders P P, DeChang W, Chao L Y
Chem Biol Interact. 1986 Jun;58(3):319-31. doi: 10.1016/s0009-2797(86)80106-5.
Decomposition of the antitumor agent 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC, Dacarbazine) produces several potentially toxic compounds, the concentration of which depend on incubation parameters such as pH, temperature and illumination. The action of DTIC on chinese hamster ovary (CHO) cell clone formation in the dark (7-8-day incubation) reflects the slow formation of 2-azahypoxanthine. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT, EC 2.4.2.8)-deficient cells are resistant to DTIC under these conditions, reflecting their inability to utilize 2-azahypoxanthine. The toxicity of DTIC in conventional survival experiments (1-2-h exposure to drug) is dependent upon illumination and is highly influenced by the pH of the medium. Toxicity of DTIC in these experiments appears to reflect rapid accumulation of the immediate photodecomposition product of the drug, 4-diazoimidazole-5-carboxamide (DZC), since HGPRT-deficient cells are not resistant to DTIC under these conditions. The biologically initiated pathway of DTIC action (enzymatic hydroxylation) has little, if any, role in the action of this agent toward cultured CHO cells.
抗肿瘤药物5-(3,3-二甲基-1-三氮烯)咪唑-4-甲酰胺（DTIC，达卡巴嗪）的分解会产生几种潜在的有毒化合物，其浓度取决于孵育参数，如pH值、温度和光照。DTIC在黑暗中（7-8天孵育）对中国仓鼠卵巢（CHO）细胞克隆形成的作用反映了2-氮杂次黄嘌呤的缓慢形成。在这些条件下，次黄嘌呤-鸟嘌呤磷酸核糖转移酶（HGPRT，EC 2.4.2.8）缺陷细胞对DTIC具有抗性，这反映了它们无法利用2-氮杂次黄嘌呤。在传统的存活实验中（药物暴露1-2小时），DTIC的毒性取决于光照，并且受到培养基pH值的高度影响。在这些实验中，DTIC的毒性似乎反映了药物直接光解产物4-重氮咪唑-5-甲酰胺（DZC）的快速积累，因为在这些条件下HGPRT缺陷细胞对DTIC没有抗性。DTIC作用的生物起始途径（酶促羟基化）在该药物对培养的CHO细胞的作用中几乎没有作用（如果有作用的话）。
