Cussac C, Mounetou E, Rapp M, Madelmont J C, Maurizis J C, Labarre P, Chollet P, Chabard J L, Godeneche D, Baudry J P
Instruments et Médicaments de France, Cournon.
Drug Metab Dispos. 1994 Jul-Aug;22(4):637-42.
Tumor resistances to chloroethylnitrosourea (CENU) are mainly due to O6-alkylguanine-DNA alkyltransferase (AGT). Our laboratory has synthesized a new water-soluble AGT inhibitor. O6-benzyl-N-acetylguanosine (BNAG). We have shown that this compound is able to deplete AGT activity on M4Beu human melanoma cells and to enhance the antitumor power of CENU N'-[2-chloroethyl]-N-[2-(methylsulfonyl)ethyl]-N'-nitrosourea (cystemustine) towards the M4Beu melanoma grafted on nude mice. With a view to determining the best combination BNAG/CENUs conditions, we have studied the distribution and metabolism of BNAG in nude mice bearing M4Beu human melanoma. BNAG, labelled with carbon-14 on the benzyl group, was administered by single i.v. dose of 40 mg/kg. Blood analysis showed that the main radioactive compound was unchanged molecule, and only a small part was found as hippuric acid resulting from the metabolic cleavage of the benzyl group. BNAG and hippuric acid were mainly eliminated in the urine. Unchanged BNAG blood kinetics showed three phases: blood epuration (t1/2 (1) = 13 min), reabsorption and elimination (t1/2 (2) = 1.7 hr). This kinetic profile is probably due to an enterohepatic cycle. BNAG is distributed in several tissues (kidney, liver, skin, duodenum, colon, tumor) but not in the central nervous system, suggesting a poor blood-brain crossing. Because an important part of the administered dose is not metabolized, high unchanged BNAG level remains in most tissues, including M4Beu tumor, and AGT depletion can occur several hours after dosing.
肿瘤对氯乙基亚硝基脲（CENU）的耐药性主要归因于O6-烷基鸟嘌呤-DNA烷基转移酶（AGT）。我们实验室合成了一种新型水溶性AGT抑制剂，即O6-苄基-N-乙酰鸟苷（BNAG）。我们已经证明，该化合物能够降低M4Beu人黑色素瘤细胞中的AGT活性，并增强CENU N'-[2-氯乙基]-N-[2-(甲基磺酰基)乙基]-N'-亚硝基脲（胱胺芥）对裸鼠移植的M4Beu黑色素瘤的抗肿瘤能力。为了确定BNAG/CENUs的最佳联合使用条件，我们研究了BNAG在荷M4Beu人黑色素瘤裸鼠体内的分布和代谢。用苄基上标记有碳-14的BNAG，以40mg/kg的单次静脉注射剂量给药。血液分析表明，主要的放射性化合物是未变化的分子，仅发现一小部分是苄基代谢裂解产生的马尿酸。BNAG和马尿酸主要通过尿液排出。未变化的BNAG血液动力学显示出三个阶段：血液净化（t1/2(1)=13分钟）、重吸收和消除（t1/2(2)=1.7小时）。这种动力学特征可能归因于肠肝循环。BNAG分布于多个组织（肾脏、肝脏、皮肤、十二指肠、结肠、肿瘤），但未分布于中枢神经系统，这表明其血脑屏障通透性较差。由于给药剂量的一大部分未被代谢，在大多数组织（包括M4Beu肿瘤）中仍保留着高浓度的未变化的BNAG，并且在给药后数小时可发生AGT耗竭。
