Optimal antidiarrhea treatment for antitumor agent irinotecan hydrochloride (CPT-11)-induced delayed diarrhea
Optimal antidiarrhea treatment for antitumor agent irinotecan hydrochloride (CPT-11)-induced delayed diarrhea
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DOI：
10.1007/s00280-006-0187-8
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发表时间：
2006-10-01
影响因子：
3
通讯作者：
Kamataki, T.
中科院分区：
文献类型：
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作者：
Takasuna, K.;Hagiwara, T.;Kamataki, T.
目的：抗肿瘤喜树碱衍生物CPT-11已被证明是一种广谱的实体瘤恶性肿瘤，但其严重的腹泻往往限制了其更广泛的使用。我们已经从大鼠模型中证明，肠道β-葡萄糖醛酸苷酶可能通过管腔SN-38葡萄糖醛酸苷的解结合在CPT-11诱导的迟发性腹泻的发生中发挥关键作用，并且通过抗生素或给予TJ-14（一种含有β-葡萄糖醛酸苷酶抑制剂黄芩苷的汉方药物）消除肠道微生物群落发挥保护作用。在本研究中，我们评估了几种潜在治疗方法在大鼠模型中的疗效，以阐明哪种治疗CPT-11诱导的迟发性腹泻最有希望。方法和结果：口服给药（第-1至4天每天两次）链霉素20 mg/kg和青霉素10 mg/kg（Str/Pen）、新霉素20 mg/kg和杆菌肽10 mg/kg（Neo/Bac），这两种药物几乎完全抑制粪便β-葡萄糖醛酸酶活性，或TJ-14 1，000 mg/kg改善CPT-11（60 mg/kg，第1 - 4天静脉注射）诱导的体重下降和迟发性腹泻症状的程度相似。活性炭（1，000 mg/kg p.o.从第-1天至第4天每天两次）。在使用携带乳腺癌的大鼠（步行者256-TC）的单独实验中，TJ-14、Neo/Bac和活性炭在相同剂量方案下改善CPT-11诱导的肠毒性，而不降低CPT-11的抗肿瘤活性。相比之下，口服给予（每天两次）环孢菌素A（50 mg/kg）（一种P-糖蛋白和cMOAT/MRP 2抑制剂）或丙戊酸（200 mg/kg）（一种UDP-葡萄糖醛酸基转移酶抑制剂）加重了肠道毒性，但未改变CPT-11的抗肿瘤活性。结论：结果清楚地证明了Neo/Bac、Str/Pen和TJ-14改善CPT-11诱导的迟发性腹泻的能力，活性炭的能力较小但显著，表明减少肠道暴露于管腔SN-38的治疗对于改善CPT-11诱导的肠道毒性是有价值的。相反，影响CPT-11及其代谢产物胆汁排泄的治疗可能会产生不良结果。
Purpose: An antitumor camptothecin derivative CPT-11 has proven a broad spectrum of solid tumor malignancy, but its severe diarrhea has often limited its more widespread use. We have demonstrated from a rat model that intestinal beta-glucuronidase may play a key role in the development of CPT-11-induced delayed diarrhea by the deconjugation of the luminal SN-38 glucuronide, and the elimination of the intestinal microflora by antibiotics or dosing of TJ-14, a Kampo medicine that contains beta-glucuronidase inhibitor baicalin, exerted a protective effect. In the present study, we assessed the efficacy of several potential treatments in our rat model to clarify which is the most promising treatment for CPT-11-induced delayed diarrhea. Methods and results: Oral dosing (twice daily from days -1 to 4) of streptomycin 20 mg/kg and penicillin 10 mg/kg (Str/Pen), neomycin 20 mg/kg and bacitracin 10 mg/kg (Neo/Bac), both of which inhibited almost completely the fecal beta-glucuronidase activity, or TJ-14 1,000 mg/kg improved the decrease in body weight and the delayed diarrhea symptoms induced by CPT-11 (60 mg/kg i.v. from days 1 to 4) to a similar extent. The efficacy was less but significant in activated charcoal (1,000 mg/kg p.o. twice daily from days -1 to 4). In a separate experiment using rats bearing breast cancer (Walker 256-TC), TJ-14, Neo/Bac, and charcoal at the same dose regimen improved CPT-11-induced intestinal toxicity without reducing CPT-11's antitumor activity. In contrast, oral dosing (twice a day) of cyclosporin A (50 mg/kg), a P-glycoprotein and cMOAT/MRP2 inhibitor or valproic acid (200 mg/kg), a UDP-glucuronosyltranferase inhibitor, exacerbated the intestinal toxicity without modifying CPT-11's antitumor activity. Conclusions: The result clearly demonstrated the ability of Neo/Bac, Str/Pen, and TJ-14, less but significant ability of activated charcoal, to ameliorate CPT-11-induced delayed-onset diarrhea, suggesting the treatments decreasing the exposure of the intestines to the luminal SN-38 are valuable for improvement of CPT-11-induced intestinal toxicity. In contrast, the treatments affecting the biliary excretion of CPT-11 and its metabolites might have undesirable results.