The number of intestinal bacteria is not critical for the enhancement of antitumor activity and reduction of intestinal toxicity of irinotecan by the Chinese herbal medicine PHY906 (KD018).
The number of intestinal bacteria is not critical for the enhancement of antitumor activity and reduction of intestinal toxicity of irinotecan by the Chinese herbal medicine PHY906 (KD018).
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DOI：
10.1186/1472-6882-14-490
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发表时间：
2014-12-15
影响因子：
--
通讯作者：
Cheng YC
中科院分区：
文献类型：
--
作者：
Lam W;Jiang Z;Guan F;Hu R;Liu SH;Chu E;Cheng YC
四味中药PHY 906（KD 018）已被证明可以增强伊立替康（CPT-11）对结肠癌肿瘤同种异体移植物的体内抗肿瘤活性，并减轻CPT-11引起的肠道毒性。由于肠道细菌可以代谢CPT-11和PHY 906，我们研究了肠道细菌是否在PHY 906在小鼠结肠-38荷瘤小鼠中的体内活性中起关键作用。在用PHY 906和/或CPT-11处理之前和期间，使用链霉素/新霉素消耗肠细菌10天。使用16 S DNA组特异性引物的qPCR来定量主要肠道细菌的水平。PHY 906和抗生素治疗都改变了肠道细菌种类的概况：乳杆菌/肠球菌、拟杆菌、纤细梭菌和大肠杆菌。直肠型C.球菌。抗生素处理没有改变PHY 906增强CPT-11的抗肿瘤活性的能力。单独抗生素治疗部分减少CPT-11治疗小鼠的动物体重减轻。然而，PHY 906治疗能够防止CPT-11/抗生素治疗组中的体重减轻。肠的H&E和PCNA染色显示抗生素治疗部分地减轻CPT-11引起的肠损伤，但不如PHY 906治疗有效。抗生素治疗加PHY 906赋予肠组织结构最有效的保护免受CPT-11的损伤。PHY 906和抗生素治疗均抑制CPT-11相关的炎症过程，包括肠中嗜中性粒细胞浸润、肠中MCP 1和TNF-α mRNA表达以及血浆中促炎细胞因子G-CSF和MCP 1蛋白的表达。然而，尽管抗生素治疗抑制了两种重要的肠祖细胞/干细胞标志物Olfm 4和Lgr 5的mRNA表达，但PHY 906治疗导致这两种干细胞标志物的表达增强。肠道细菌群的改变不影响PHY 906增强CPT-11抗肿瘤活性或降低与CPT-11治疗相关的肠道毒性的能力。肠道细菌的主要种类似乎在PHY 906增强CPT-11在荷瘤小鼠中的治疗指数中不起作用。因此，具有不同肠道细菌谱的患者仍然可以受益于PHY 906治疗以及CPT-11。
The four-herb Chinese medicine PHY906(KD018) has been shown to both enhance the in vivo antitumor activity of irinotecan (CPT-11) against colon cancer tumor allografts and alleviate intestinal toxicity caused by CPT-11. Since intestinal bacteria can metabolize CPT-11 and PHY906, we investigated whether intestinal bacteria play a critical role in the in vivo activity of PHY906 in murine Colon-38 tumor-bearing mice. Intestinal bacteria were depleted using streptomycin/neomycin for 10 days before and during treatment with PHY906 and/or CPT-11. qPCR using 16S DNA group-specific primers was used to quantify the levels of the major intestinal bacteria. Both PHY906 and antibiotic treatment changed the profile of intestinal bacteria species: Lactobacillus/Enterococcus, Bacteroides, Clostridium leptum, and E. rectale/C. coccoides. Antibiotic treatment did not alter the ability of PHY906 to enhance the antitumor activity of CPT-11. Antibiotic treatment alone partially reduced animal body weight loss in CPT-11-treated mice. However, PHY906 treatment was able to protect against the body weight loss in the CPT-11/antibiotic treatment group. H&E and PCNA staining of intestine showed that antibiotic treatment partially reduced the intestinal damage caused by CPT-11 but not as effectively as PHY906 treatment. Antibiotic treatment plus PHY906 conferred the most effective protection of intestine histological structure against damage by CPT-11. Both PHY906 and antibiotic treatment inhibited CPT-11-associated inflammatory processes, including infiltration of the intestine by neutrophils, MCP1 and TNF-alpha mRNA expression in the intestine, and expression of pro-inflammatory cytokines G-CSF and MCP1 proteins in the plasma. However, whereas antibiotic treatment suppressed the mRNA expression of two important intestinal progenitor/stem cell markers, Olfm4 and Lgr5, PHY906 treatment resulted in enhanced expression of these two stem cell markers. Alterations in the population of intestinal bacteria did not affect the abilities of PHY906 to enhance CPT-11 antitumor activity or reduce the intestinal toxicity associated with CPT-11 treatment. The major species of intestinal bacteria do not appear to play a role in PHY906’s enhancement of the therapeutic index of CPT-11 in tumor-bearing mice. Thus, patients with different intestinal bacterial profiles may still benefit from PHY906 treatment alongside CPT-11.
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影响因子：
5.8
作者：
De Jong, Floris A.;Kehrer, Diederik F. S.;De Jonge, Maja J. A.
通讯作者：
De Jonge, Maja J. A.
影响因子：
45.3
作者：
Benson, AB;Ajani, JA;Wadler, S
通讯作者：
Wadler, S
影响因子：
3
作者：
Desai, AA;Kindler, HL;Vokes, EE
通讯作者：
Vokes, EE
影响因子：
3.5
作者：
Karthaus, M;Ballo, H;Kleeberg, U
通讯作者：
Kleeberg, U
影响因子：
45.3
作者：
Herben, VMM;Schellens, JHM;Huinink, WWT
通讯作者：
Huinink, WWT