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Optimal antidiarrhea treatment for antitumor agent irinotecan hydrochloride (CPT-11)-induced delayed diarrhea.

AbstractPURPOSE:
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.
AuthorsK Takasuna, T Hagiwara, K Watanabe, S Onose, S Yoshida, E Kumazawa, E Nagai, T Kamataki
JournalCancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 58 Issue 4 Pg. 494-503 (Oct 2006) ISSN: 0344-5704 [Print] Germany
PMID16437251 (Publication Type: Journal Article)
Chemical References
  • Antidiarrheals
  • Antineoplastic Agents, Phytogenic
  • Enzyme Inhibitors
  • Flavonoids
  • Penicillins
  • baicalin
  • Irinotecan
  • Glucuronidase
  • Camptothecin
  • Streptomycin
Topics
  • Animals
  • Antidiarrheals (therapeutic use)
  • Antineoplastic Agents, Phytogenic (toxicity)
  • Camptothecin (analogs & derivatives, toxicity)
  • Diarrhea (chemically induced, drug therapy, prevention & control)
  • Enzyme Inhibitors (pharmacology, therapeutic use)
  • Flavonoids (therapeutic use)
  • Glucuronidase (antagonists & inhibitors, metabolism)
  • Intestines (enzymology)
  • Irinotecan
  • Male
  • Medicine, Kampo
  • Penicillins (therapeutic use)
  • Rats
  • Rats, Wistar
  • Streptomycin (therapeutic use)

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