Tricot G J, Jayaram H N, Lapis E, Natsumeda Y, Nichols C R, Kneebone P, Heerema N, Weber G, Hoffman R
Department of Medicine, Indiana University School of Medicine, Indianapolis 46223.
Cancer Res. 1989 Jul 1;49(13):3696-701.
Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193), a selective inhibitor of the activity of IMP dehydrogenase (EC 1.1.1.205), the rate-limiting enzyme of de novo GTP biosynthesis, provided in end stage leukemic patients a rapid decrease of IMP dehydrogenase activity and GTP concentration in the blast cells and a subsequent decline in blast cell count. Sixteen consecutive patients with end stage acute nonlymphocytic leukemia or myeloid blast crisis of chronic granulocytic leukemia were treated with tiazofurin. Allopurinol was also given to inhibit xanthine oxidase activity to decrease uric acid excretion and to elevate the serum concentration of hypoxanthine, which should competitively inhibit the activity of hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8), the salvage enzyme of guanylate synthesis. Assays of IMP dehydrogenase activity and GTP concentration in leukemic cells provided a method to monitor the impact of tiazofurin and allopurinol and to adjust the drug doses. In this group of patients with poor prognosis, five attained a complete hematological remission and one showed a hematological improvement. A marked antileukemic effect was seen in two other patients. All five evaluable patients with myeloid blast crisis of chronic granulocytic leukemia reentered the chronic phase of their disease. Five patients with acute nonlymphocytic leukemia were refractory to tiazofurin and three were unevaluable for hematological effect because of early severe complications. Responses with intermittent 5- to 15-day courses of tiazofurin lasted 3-10 months. Tiazofurin had a clear antiproliferative effect, but the pattern of hematological response indicated that it appeared to induce differentiation of leukemic cells. In spite of toxicity with severe or life-threatening complications in 11 of 16 patients, tiazofurin was better tolerated in most patients than other antileukemic treatment modalities and provided a rational, biochemically targeted, and biochemically monitored chemotherapy which should be of interest in the treatment of leukemias and as a paradigm in enzyme pattern-targeted chemotherapy.
硫唑嘌呤（2-β-D-呋喃核糖基噻唑-4-甲酰胺，NSC 286193）是肌苷酸脱氢酶（EC 1.1.1.205）活性的选择性抑制剂，肌苷酸脱氢酶是从头合成GTP的限速酶。在晚期白血病患者中，硫唑嘌呤可使原始细胞中的肌苷酸脱氢酶活性和GTP浓度迅速降低，随后原始细胞计数下降。16例晚期急性非淋巴细胞白血病或慢性粒细胞白血病髓系原始细胞危象患者接受了硫唑嘌呤治疗。同时给予别嘌呤醇以抑制黄嘌呤氧化酶活性，减少尿酸排泄并提高次黄嘌呤的血清浓度，次黄嘌呤应竞争性抑制次黄嘌呤-鸟嘌呤磷酸核糖转移酶（EC 2.4.2.8）的活性，该酶是鸟苷酸合成的补救酶。对白血病细胞中肌苷酸脱氢酶活性和GTP浓度的检测提供了一种监测硫唑嘌呤和别嘌呤醇作用并调整药物剂量的方法。在这组预后不良的患者中，5例达到完全血液学缓解，1例显示血液学改善。另外2例患者出现明显的抗白血病作用。所有5例可评估的慢性粒细胞白血病髓系原始细胞危象患者均重新进入疾病的慢性期。5例急性非淋巴细胞白血病患者对硫唑嘌呤耐药，3例因早期严重并发症而无法评估血液学疗效。硫唑嘌呤间歇性5至15天疗程的反应持续3至10个月。硫唑嘌呤具有明显的抗增殖作用，但血液学反应模式表明它似乎能诱导白血病细胞分化。尽管16例患者中有11例出现严重或危及生命的并发症毒性，但大多数患者对硫唑嘌呤的耐受性优于其他抗白血病治疗方式，并提供了一种合理的、以生物化学为靶点且可进行生物化学监测的化疗方法，这在白血病治疗中应具有重要意义，并可作为酶模式靶向化疗的范例。
