Bayever E, Iversen P L, Bishop M R, Sharp J G, Tewary H K, Arneson M A, Pirruccello S J, Ruddon R W, Kessinger A, Zon G
Department of Pediatrics, University of Nebraska Medical Center, Omaha 68198.
Antisense Res Dev. 1993 Winter;3(4):383-90. doi: 10.1089/ard.1993.3.383.
A synthetic phosphorothioate oligonucleotide was administered systemically to five patients with either relapsed or refractory acute myelogenous leukemia (AML), or myelodysplastic syndrome (MDS). Patients received a 10-day continuous intravenous infusion of this compound, which is complementary to p53 mRNA. No major toxicity attributable to a dose of 0.05 mg/kg/hr was observed. A range of approximately 9 to 18% of the administered dose was recovered in the urine as intact oligonucleotide. Evaluation of malignant cells recovered from bone marrow and peripheral blood at intervals before, during, and after treatment reveals no enhanced growth potential following oligonucleotide administration. Hence, a phosphorothioate oligonucleotide complementary to p53 mRNA can be administered at this dose level to humans without major toxicity. Higher doses need to be evaluated for toxicity and potential clinical efficacy.
一种合成的硫代磷酸酯寡核苷酸被系统地给予了5例复发或难治性急性髓性白血病（AML）或骨髓增生异常综合征（MDS）患者。患者接受了为期10天的该化合物持续静脉输注，该化合物与p53 mRNA互补。未观察到归因于0.05 mg/kg/hr剂量的重大毒性。约9%至18%的给药剂量以完整寡核苷酸的形式在尿液中回收。在治疗前、治疗期间和治疗后的不同时间对从骨髓和外周血中回收的恶性细胞进行评估，结果显示给予寡核苷酸后恶性细胞的生长潜力未增强。因此，与p53 mRNA互补的硫代磷酸酯寡核苷酸可以在该剂量水平给予人类而无重大毒性。需要对更高剂量进行毒性和潜在临床疗效评估。
