The influence of the schedule and the dose of gemcitabine on the anti-tumour efficacy in experimental human cancer.
The influence of the schedule and the dose of gemcitabine on the anti-tumour efficacy in experimental human cancer.
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DOI：
10.1038/bjc.1993.285
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发表时间：
1993-07
影响因子：
8.8
通讯作者：
Pinedo, H M
中科院分区：
文献类型：
--
作者：
Boven, E;Schipper, H;Erkelens, C A;Hatty, S A;Pinedo, H M
吉西他滨是一种新的核苷类似物，在裸鼠体内多种成熟的人软组织肉瘤和卵巢癌异种移植物中评估了其治疗效果。所选肿瘤系具有不同的组织学亚型、生长速度和对常规细胞抑制剂的敏感性。根据平均体重减轻5%至15%而设计的三种不同剂量和时间表分别为每日3.5 mg kg-1 x 4、每3天120 mg kg-1 x 4和每周240 mg kg-1 x 2，最终分别导致19%、10%和4%的毒性死亡。在2/4的软组织肉瘤和4/6的卵巢癌细胞系中，每周计划诱导>或= 50%的生长抑制，而在3种卵巢癌细胞系中，获得>或= 75%的生长抑制。吉西他滨的抗肿瘤效果似乎与之前在相同肿瘤系中测试的常规药物相似，甚至更好。与每3天给药相比，每周给药和每天给药在5/7和3/3肿瘤系中效果较差（P < 0.001）。在另一项实验中，在对吉西他滨不同敏感性的三种人类肿瘤系中，每周注射240 mg kg-1 x 6与相同时间表的较低剂量120 mg kg-1或60 mg kg-1相比，没有导致生长抑制百分比的显着增加。然而，240 mg kg-1 /周× 6的治疗方案在2/3的肿瘤系中比相同剂量的每2周× 3的治疗效果更好（P < 0.05）。吉西他滨的临床前活性表明，该药物可以诱导软组织肉瘤和卵巢癌患者的反应。我们的结果进一步表明，吉西他滨在实体肿瘤类型中的临床试验应该基于时间表而不是剂量依赖来设计。
The therapeutic efficacy of gemcitabine, a new nucleoside analogue, was assessed in a variety of well-established human soft tissue sarcoma and ovarian cancer xenografts grown s.c. in nude mice. Tumour lines selected had different histological subtypes, growth rates and sensitivities to conventional cytostatic agents. The three different doses and schedules designed on the basis of a mean weight loss between 5% and 15% were i.p. injections of daily 3.5 mg kg-1 x 4, every 3 days 120 mg kg-1 x 4, and weekly 240 mg kg-1 x 2, which ultimately resulted in 19%, 10% and 4% toxic deaths, respectively. The weekly schedule induced > or = 50% growth inhibition in 2/4 soft tissue sarcoma and 4/6 ovarian cancer lines, while in three ovarian cancer lines > or = 75% growth inhibition was obtained. The anti-tumour effects of gemcitabine appeared to be similar or even better than previous data with conventional drugs tested in the same tumour lines. In comparison with the every 3 days schedule, the weekly and the daily schedule were less effective in 5/7 and 3/3 tumour lines (P < 0.001), respectively. In another experiment in three human tumour lines selected for their differential sensitivity to gemcitabine, weekly injections of 240 mg kg-1 x 6 did not result in a significant increase in the percentages of growth inhibition when compared to lower doses of 120 mg kg-1 or 60 mg kg-1 in the same schedule. However, the 240 mg kg-1 weekly x 6 schedule showed superior effects in 2/3 tumour lines in comparison with the same dose given every 2 weeks x 3 (P < 0.05). The preclinical activity of gemcitabine suggests that the drug can induce responses in soft tissue sarcoma and ovarian cancer patients. Our results further indicate that clinical trials of gemcitabine in solid tumour types should be designed on the basis of a schedule rather than a dose dependence.