Politi P M, Xie F, Dahut W, Ford H, Kelley J A, Bastian A, Setser A, Allegra C J, Chen A P, Hamilton J M
NCI-Navy Medical Oncology Branch, National Cancer Institute, Bethesda, MD 20889, USA.
Cancer Chemother Pharmacol. 1995;36(6):513-23. doi: 10.1007/BF00685802.
Cyclopentenyl cytosine (CPE-C) is an investigational drug that is active against human solid tumor xenografts. The 5'-triphosphate of CPE-C inhibits CTP synthase, and depletes CTP and dCTP pools. We conducted a phase I clinical trial of CPE-C given as a 24-h continuous i.v. infusion every 3 weeks in 26 adults with solid tumors. The starting dose rate, 1 mg/m2 per h, was selected on the basis of both preclinical studies and pharmacokinetic data from two patients obtained after a test dose of 24 mg/m2 CPE-C as an i.v. bolus. Dose escalation was guided by clinical toxicity. A total of 87 cycles were given, and ten patients received four or more cycles. The mean CPE-C steady-state plasma levels (Cpss) increased linearly from 0.4 microM to 3.1 microM at dose levels ranging from 1 to 5.9 mg/m2 per h (actual body weight); the mean total body clearance was 146 +/- 38 ml/min per m2. CPE-C was eliminated by both renal excretion of intact drug and deamination to cyclopentenyl uracil in an apparent 2:1 ratio. CTP synthase activity in intact bone marrow mononuclear cells was inhibited by 58% to 100% at 22 h compared to matched pretreatment samples at all CPE-C dose levels. When all data were combined, flux through CTP synthase was decreased by 89.6% +/- 3.1% at 22 h (mean +/- SE, n = 16), and remained inhibited by 67.6% +/- 7.7% (n = 10) for at least 24 h post-CPE-C infusion. Granulocyte and platelet toxicities were dose-dependent, and dose-limiting myelosuppression occurred during the initial cycle in two of three patients treated with 5.9 mg/m2 per h. Four of 11 patients (4 of 20 cycles) who received 4.7 mg/m2 per h CPE-C experienced hypotension 24-48 h after completion of the CPE-C infusion during their first (n = 2), third (n = 1) and sixth cycles (n = 1), respectively. Two of these patients died with refractory hypotension despite aggressive hydration and cardiopulmonary resuscitation. One of 12 patients (28 total cycles) treated with 3.5 mg/m2 per h CPE-C experienced orthostatic hypotension during cycle 1, and this patient had a second episode of orthostatic hypotension at a lower dose (3.0 mg/m2 per h). Hypotension was not seen in patients receiving < or = 2.5 mg/m2 per h CPE-C.(ABSTRACT TRUNCATED AT 400 WORDS)
环戊烯基胞嘧啶（CPE-C）是一种用于研究的药物，对人实体瘤异种移植物具有活性。CPE-C的5'-三磷酸抑制CTP合酶，并消耗CTP和dCTP库。我们对26例患有实体瘤的成年人进行了CPE-C的I期临床试验，每3周进行一次24小时持续静脉输注。起始剂量率为每小时1mg/m²，这是根据临床前研究以及在给予24mg/m² CPE-C静脉推注的试验剂量后从两名患者获得的药代动力学数据选定的。剂量递增以临床毒性为指导。共进行了87个周期，10名患者接受了四个或更多周期的治疗。在每小时1至5.9mg/m²（实际体重）的剂量水平下，CPE-C的平均稳态血浆水平（Cpss）从0.4μM线性增加至3.1μM；平均全身清除率为每平方米146±38ml/min。CPE-C通过完整药物的肾排泄和脱氨生成环戊烯基尿嘧啶两种方式消除，其比例明显为2:1。在所有CPE-C剂量水平下，与匹配的预处理样本相比，完整骨髓单核细胞中的CTP合酶活性在22小时时被抑制58%至100%。当所有数据合并时，在22小时时通过CTP合酶的通量降低了89.6%±3.1%（平均值±标准误，n = 16），并且在CPE-C输注后至少24小时内仍被抑制67.6%±7.7%（n = 10）。粒细胞和血小板毒性呈剂量依赖性，在接受每小时5.9mg/m²治疗的三名患者中的两名患者的初始周期中发生了剂量限制性骨髓抑制。接受每小时4.7mg/m² CPE-C的11名患者中的4名（20个周期中的4个）在其第一个（n = 2）、第三个（n = 1）和第六个周期（n = 1）中，在CPE-C输注完成后24 - 48小时出现低血压。尽管积极补液和进行心肺复苏，其中两名患者死于顽固性低血压。在接受每小时3.5mg/m² CPE-C治疗的12名患者中的1名（共28个周期）在第1周期出现体位性低血压，并且该患者在较低剂量（每小时3.0mg/m²）时再次出现体位性低血压。在接受每小时≤2.5mg/m² CPE-C的患者中未观察到低血压。（摘要截断于400字）
