Kovach J S, Rubin J, Creagan E T, Schutt A J, Kvols L K, Svingen P A, Hu T C
Cancer Res. 1986 Nov;46(11):5959-62.
For almost 30 years, 6-thioguanine (6-TG) has been administered p.o. for treatment of various human cancers, especially leukemias, even though the systemic availability of the drug given p.o. is known to be low and highly variable. Parenterally administered 6-TG has been studied in detail in humans only on a single-day intermittent schedule, although multiple-day intermittent schedules are known to produce maximal cytotoxic effects in several animal species. To develop a multiple-day regimen for parenteral 6-TG therapy, we carried out a dose-seeking and pharmacokinetic study of the drug given i.v. daily for 5 days in patients with various refractory advanced solid tumors. Dose-limiting myelosuppression without other significant toxicity occurred at 55-65 mg/m2 daily for 5 days. After i.v. administration at 65 mg/m2, the mean peak plasma concentration of 6-TG ranged from 6-10 microM. These concentrations are 8-300 times greater than peak plasma concentrations of 6-TG in plasma reported to occur after p.o. administration at 100 mg/m2. We suggest that the antitumor activity of 6-TG be reassessed against human cancers in regimens of i.v. administration on multiple-day intermittent schedules.
近30年来，6-硫鸟嘌呤（6-TG）一直通过口服给药用于治疗各种人类癌症，尤其是白血病，尽管已知口服该药物的全身可用性较低且高度可变。虽然已知多日间歇给药方案在几种动物物种中可产生最大细胞毒性作用，但仅在单日间歇给药方案下对人类进行了详细的肠外给予6-TG的研究。为了开发一种用于肠外6-TG治疗的多日方案，我们对患有各种难治性晚期实体瘤的患者进行了一项剂量探索和药代动力学研究，静脉注射该药物，连续5天每天给药。连续5天每天以55-65mg/m²给药时出现剂量限制性骨髓抑制，无其他明显毒性。以65mg/m²静脉给药后，6-TG的平均血浆峰值浓度范围为6-10μM。这些浓度比口服100mg/m²后报告的血浆中6-TG的血浆峰值浓度高8-300倍。我们建议在多日间歇给药方案的静脉给药方案中重新评估6-TG对人类癌症的抗肿瘤活性。
