Abstract | PURPOSE: 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.
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Authors | K Takasuna, T Hagiwara, K Watanabe, S Onose, S Yoshida, E Kumazawa, E Nagai, T Kamataki |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 58
Issue 4
Pg. 494-503
(Oct 2006)
ISSN: 0344-5704 [Print] Germany |
PMID | 16437251
(Publication Type: Journal Article)
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Chemical References |
- Antidiarrheals
- Antineoplastic Agents, Phytogenic
- Enzyme Inhibitors
- Flavonoids
- Penicillins
- baicalin
- Irinotecan
- Glucuronidase
- Camptothecin
- Streptomycin
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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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