title: 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).
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.forename: Wing
authors.initials: W
authors.lastname: Lam
authors.forename: Zaoli
authors.initials: Z
authors.lastname: Jiang
authors.forename: Fulan
authors.initials: F
authors.lastname: Guan
authors.forename: Rong
authors.initials: R
authors.lastname: Hu
authors.forename: Shwu-Huey
authors.initials: SH
authors.lastname: Liu
authors.forename: Edward
authors.initials: E
authors.lastname: Chu
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA. ycccheng@yale.edu.
authors.forename: Yung-Chi
authors.initials: YC
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001419:Bacteria / Q000187:drug effects* / Q000254:growth & development; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000382:microbiology / Q000473:pathology; D000077146:Irinotecan; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects; D008517:Phytotherapy; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D000972:Antineoplastic Agents, Phytogenic; D004365:Drugs, Chinese Herbal; C116884:LGR5 protein, human; C454127:OLFM4 protein, human; C476037:PHY 906; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; D000077146:Irinotecan; D002166:Camptothecin