α-二氟甲基鸟氨酸的随机I期化学预防剂量探索研究

Randomized phase I chemoprevention dose-seeking study of alpha-difluoromethylornithine.

作者信息

Love R R, Carbone P P, Verma A K, Gilmore D, Carey P, Tutsch K D, Pomplun M, Wilding G

机构信息

University of Wisconsin Comprehensive Cancer Center, Madison.

出版信息

J Natl Cancer Inst. 1993 May 5;85(9):732-7. doi: 10.1093/jnci/85.9.732.

DOI:10.1093/jnci/85.9.732

PMID:8478959

Abstract

BACKGROUND

alpha-Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase (ODC), the key enzyme in mammalian polyamine biosynthesis. Levels of ODC are closely related to tumor promotion, and inhibition of ODC is associated with suppression of tumor development in laboratory animals. DFMO has shown a dose-response effect in tumor inhibition in mice.

PURPOSE

A randomized phase I study of DFMO was conducted to determine the lowest daily oral dose that can achieve at least 50% inhibition of ODC activity induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in human skin, with minimal clinical toxicity (grade 1 or lower; Eastern Cooperative Oncology Group [ECOG]).

METHODS

Cancer patients entered in steps 1 and 2 of the study had been treated and had no clinical evidence of cancer. In step 1, 13 patients received 0.125, 0.25, 0.5, or 0.75 g/m2 DFMO four times a day. In step 2, 13 patients received 0.125 or 0.25 g/m2 four times a day or 0.5 or 1.0 g/m2 every day. The 26 patients treated in steps 1 and 2 (range, < 1-6 months) had colon, prostate, or bladder cancer. In step 3, six cancer-free subjects at risk for colorectal cancer received 0.5 g/m2 every day for 5-12 months. To evaluate the effectiveness of DFMO in reducing TPA-induced ODC activity, we calculated the percent change from pretreatment ODC levels in skin biopsy specimens and the percentage of subjects with at least a 50% reduction in ODC levels.

RESULTS

In step 1 of the study, treatment-limiting audiotoxicity was observed at the three highest doses. Because the only dose with no major toxic effects in step 2 was 0.5 g/m2 every day, that dose was administered in step 3, with no major toxic effects. Seven subjects treated with 0.5 g/m2 every day had pretreatment ODC levels in the normal range; five averaged a reduction in ODC activity of at least 50%. DFMO had linear pharmacokinetics over the entire dose range. When 0.5 g/m2 was given every day, the peak plasma concentration was 47.1 +/- 5.1 microM at 3-4 hours (monthly mean +/- SE, 14.5 +/- 5.2 microM); half-life was 3.5 hours; and area under the curve for plasma concentration x time for a single dose of DFMO was 311 +/- 39 microM x hour.

CONCLUSIONS

These data support phase II chemoprevention studies with DFMO given at a dose of 0.5 g/m2 every day.

IMPLICATIONS

Studies investigating prevention of cancers with DFMO are under consideration.

摘要

背景

α-二氟甲基鸟氨酸（DFMO）是鸟氨酸脱羧酶（ODC）的不可逆抑制剂，ODC是哺乳动物多胺生物合成中的关键酶。ODC水平与肿瘤促进密切相关，抑制ODC与实验动物肿瘤发展的抑制有关。DFMO在小鼠肿瘤抑制中显示出剂量反应效应。

目的

进行DFMO的随机I期研究，以确定能在人体皮肤中至少50%抑制12-O-十四烷酰佛波醇-13-乙酸酯（TPA）诱导的ODC活性的最低每日口服剂量，且临床毒性最小（1级或更低；东部肿瘤协作组[ECOG]）。

方法

进入研究第1步和第2步的癌症患者已经接受过治疗且无癌症临床证据。在第1步中，13名患者每天接受4次0.125、0.25、0.5或0.75 g/m²的DFMO。在第2步中，13名患者每天接受4次0.125或0.25 g/m²或每天接受0.5或1.0 g/m²。在第1步和第2步中接受治疗的26名患者（范围，<1 - 6个月）患有结肠癌、前列腺癌或膀胱癌。在第3步中，6名有患结直肠癌风险的无癌受试者每天接受0.5 g/m²，持续5 - 12个月。为评估DFMO降低TPA诱导的ODC活性的有效性，我们计算了皮肤活检标本中ODC水平相对于预处理水平的变化百分比以及ODC水平至少降低50%的受试者百分比。

结果

在研究的第1步中，在三个最高剂量下观察到了限制治疗的耳毒性。由于第2步中唯一无重大毒性作用的剂量是每天0.5 g/m²，因此在第3步中给予该剂量，未出现重大毒性作用。7名每天接受0.5 g/m²治疗的受试者预处理ODC水平在正常范围内；5名受试者的ODC活性平均降低至少50%。DFMO在整个剂量范围内具有线性药代动力学。当每天给予0.5 g/m²时，3 - 4小时的血浆峰浓度为47.1±5.1 microM（每月均值±标准误，14.5±5.2 microM）；半衰期为3.5小时；单剂量DFMO的血浆浓度×时间曲线下面积为311±39 microM×小时。