Levi F, Horvath C, Mechkouri M, Roulon A, Bailleul F, Lemaigre G, Reinberg A, Mathe G
Institut de Cancérologie et d'Immunogénétique (CNRS UA 04-1163), Hôpital Paul-Brousse, Villejuif, France.
Eur J Cancer Clin Oncol. 1987 May;23(5):487-97. doi: 10.1016/0277-5379(87)90308-7.
Since the extent of host toxicity of cytostatics is considerably affected by dosing time, a chronopharmacologic approach was undertaken for optimizing the therapeutic index of the alkylating agent, peptichemio (PTC). In 4 studies involving a total of 463 male B6D2F1 mice, a highly statistically significant circadian rhythm characterized murine tolerance for PTC (8 or 10 mg/kg/day i.v. X 3 days). Six circadian stages were explored (3, 7, 11, 15, 19 and 23 Hours After Light Onset--HALO). Day-40 survival rate varied between 20% (PTC at 3 HALO) and 55% (PTC at 15 HALO) (chi 2 = 16.7; P less than 0.01). In each study, body weight loss was maximal in mice injected with PTC at 3 HALO and minimal in those treated at 15 HALO (P less than 0.01). In a further study involving 96 male B6D2F1 mice, the toxicity of PTC on several target tissues (bone marrow, spleen, small bowel, colon, liver, kidney and lungs) was investigated by histology and leukocyte count as a function of drug dosing time. A circadian rhythm in the susceptibility of the bone marrow, the spleen and the intestinal tract was demonstrated. Optimal murine tolerance for PTC resulted from dosing it at 15 HALO, e.g. in the first half of the activity span.
由于细胞抑制剂的宿主毒性程度受给药时间的影响很大，因此采用了时辰药理学方法来优化烷化剂培他霉素（PTC）的治疗指数。在总共涉及463只雄性B6D2F1小鼠的4项研究中，小鼠对PTC（8或10mg/kg/天静脉注射×3天）的耐受性呈现出具有高度统计学意义的昼夜节律。研究了六个昼夜阶段（光照开始后3、7、11、15、19和23小时）。第40天的生存率在20%（光照开始后3小时给予PTC）至55%（光照开始后15小时给予PTC）之间变化（χ2 = 16.7；P<0.01）。在每项研究中，光照开始后3小时注射PTC的小鼠体重减轻最大，而光照开始后15小时治疗的小鼠体重减轻最小（P<0.01）。在另一项涉及96只雄性B6D2F1小鼠的研究中，通过组织学和白细胞计数研究了PTC对几种靶组织（骨髓、脾脏、小肠、结肠、肝脏、肾脏和肺）的毒性与给药时间的关系。结果表明骨髓、脾脏和肠道的易感性存在昼夜节律。小鼠对PTC的最佳耐受性是在光照开始后15小时给药时产生的，即在活动期的前半段给药。
