Skip to main content

Advertisement

SpringerLink
Log in

A pilot study on the safety of combining chrysin, a non-absorbable inducer of UGT1A1, and irinotecan (CPT-11) to treat metastatic colorectal cancer

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose: Recently, it was shown that chrysin causes upregulation of UGT1A1 in Caco-2 intestinal cells. Therefore, we proposed that oral chrysin may reduce irinotecan (CPT-11) induced diarrhoea by shifting the SN-38G/SN-38 equilibrium towards the inactive SN-38G in the gastrointestinal mucosa. The purpose of this study was to examine the safety of combining single agent CPT-11 with chrysin. Patients and methods: Twenty patients with previously treated advanced colorectal cancer were administered chrysin twice daily for 1  week preceding and succeeding treatment with single agent CPT-11 (350 mg/m2 over 90 min every 3 weeks). Loperamide usage and bowel frequency/consistency were recorded by patients into a study diary and blood samples were collected for CPT-11 pharmacokinetic analysis. Results: There were no observable toxicities that could be attributed to chrysin use. The grades and frequency of delayed diarrhoea were mild, with only 10% of patients experiencing grade 3 toxicity. Loperamide usage was also modest with a median of 1–5 tablets per cycle (range: 0–22). Pharmacokinetic results revealed a mass ratio of plasma SN-38G/SN-38, which was very similar to historical controls (7.15±5.67, n=18). Conclusions: These findings, combined with the observation of clinical activity and grade 3/4 neutropenia in 25% of patients, suggest that combining chrysin with CPT-11 may be a safe and potentially useful means of preventing diarrhoea, although this needs to be further investigated in the setting of a randomised trial.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Abigerges D, Armand JP, Chabot GG et al. (1994) Irinotecan (CPT-11) high-dose escalation using intensive high-dose loperamide to control diarrhea. J Natl Cancer Inst 86:446–449

    Article  PubMed  CAS  Google Scholar 

  2. Ando Y, Saka H, Ando M et al (2000) Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res 60:6921

    PubMed  CAS  Google Scholar 

  3. Ando Y, Ueoka H, Sugiyama T et al (2002) Polymorphisms of UDP-glucuronosyltransferase and pharmacokinetics of irinotecan. Ther Drug Monit 24:111–116

    Article  PubMed  CAS  Google Scholar 

  4. Armand JP, Terret C, Couteau C, Rixe O (1996) CPT-11: the European experience. In: Pantazis PG, Rothenberg B, M. (eds) The camptothecins: from discovery to the patients. Academy of Sciences, New York, pp 282–291

  5. Brown G, Vukovich M, Martini E et al (2001) Effects of androstenedione-herbal supplementation on serum sex hormone concentrations in 30- to 59-year-old-men. Int J Vitam Nutr Res 71:293–301

    Article  PubMed  CAS  Google Scholar 

  6. Brown G, Vukovich M, Martini E et al (2001) Endocrine and lipid responses to chronic androstenediol-herbal supplementation in 30 to 58 year old men. J Am Coll Nutr 20:520–528

    PubMed  CAS  Google Scholar 

  7. Brown GA, Vukovich MD, Martini ER et al (2001) Effects of androstenedione-herbal supplementation on serum sex hormone concentrations in 30- to 59-year-old men. Int J Vitam Nutr Res 71: 293–301

    Article  PubMed  CAS  Google Scholar 

  8. Brown GA, Vukovich MD, Reifenrath TA et al (2000) Effects of anabolic precursors on serum testosterone concentrations and adaptations to resistance training in young men. Int J Sport Nutr Exerc Metab 10: 340–359

    PubMed  CAS  Google Scholar 

  9. Campbell DR, Kurzer MS (1993) Flavonoid inhibition of aromatase enzyme activity in human preadipocytes. J Steroid Biochem Mol Biol 46:381–388

    Article  PubMed  CAS  Google Scholar 

  10. Canal P, Gay C, Dezeuze A et al (1996) Pharmacokinetics and pharmacodynamics of irinotecan during a phase II clinical trial in colorectal cancer Pharmacology and Molecular Mechanisms Group of the European Organization for Research and Treatment of Cancer. J Clin Oncol 14:2688–2695

    PubMed  CAS  Google Scholar 

  11. Chabot GG, Abigerges D, Catimel G et al. (1995) Population pharmacokinetics and pharmacodynamics of irinotecan (CPT-11) and active metabolite SN-38 during phase I trials. Ann Oncol 6:141–151

    PubMed  CAS  Google Scholar 

  12. Cunningham D, Pyrhonen S, James RD et al (1998) Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413–1418

    Article  PubMed  CAS  Google Scholar 

  13. de Jong FA, Mathijssen RH, Xie R et al (2004) Flat-fixed dosing of irinotecan: influence on pharmacokinetic and pharmacodynamic variability. Clin Cancer Res 10:4068–4071

    Article  PubMed  Google Scholar 

  14. de Jonge MJ, Sparreboom A, Planting AS et al (2000) Phase I study of 3-week schedule of irinotecan combined with cisplatin in patients with advanced solid tumors. J Clin Oncol 18:187–194

    PubMed  Google Scholar 

  15. Dodds HM, Clarke SJ, Findlay M et al (2000) Clinical pharmacokinetics of the irinotecan metabolite 4- piperidinopiperidine and its possible clinical importance. Cancer Chemother Pharmacol 45: 9–14

    Article  PubMed  CAS  Google Scholar 

  16. Ebner T, Remmel RP, Burchell B (1993) Human bilirubin UDP-glucuronosyltransferase catalyzes the glucuronidation of ethinylestradiol. Mol Pharmacol 43:649–654

    PubMed  CAS  Google Scholar 

  17. Fuchs CS, Moore MR, Harker G et al. (2003) Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol 21:807–814

    Article  PubMed  CAS  Google Scholar 

  18. Galijatovic A, Otake Y, Walle UK, Walle T (1999) Extensive metabolism of the flavonoid chrysin by human Caco-2 and Hep G2 cells. Xenobiotica 29:1241–1256

    Article  PubMed  CAS  Google Scholar 

  19. Galijatovic A, Otake Y, Walle UK, Walle T (2001) Induction of UDP-glucuronosyltransferase UGT1A1 by the flavonoid chrysin in Caco-2 cells–potential role in carcinogen bioinactivation. Pharm Res 18: 374–379

    Article  PubMed  CAS  Google Scholar 

  20. Galijatovic A, Walle UK, Walle T (2000) Induction of UDP-glucuronosyltransferase by the flavonoids chrysin and quercetin in Caco-2 cells. Pharm Res 17:21–26

    Article  PubMed  CAS  Google Scholar 

  21. Gupta E, Lestingi TM, Mick R et al. (1994) Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea. Cancer Res 54:3723–3725

    PubMed  CAS  Google Scholar 

  22. Haaz MC, Rivory L, Jantet S et al. (1997) Glucuronidation of SN-38, the active metabolite of irinotecan, by human hepatic microsomes. Pharmacol Toxicol 80:91–96

    Article  PubMed  CAS  Google Scholar 

  23. Innocenti F, Undevia SD, Iyer L et al. (2004) Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 22:1382–1388

    Article  PubMed  CAS  Google Scholar 

  24. Iyer L, Das S, Janisch L et al. (2002) UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics 2: 43–47

    Article  CAS  Google Scholar 

  25. Iyer L, King CD, Whitington PF et al. (1998) Genetic predisposition to the metabolism of irinotecan (CPT-11) Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest 101: 847–854

    PubMed  CAS  Google Scholar 

  26. Kawato Y, Aonuma M, Hirota Y et al. (1991) Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumor effect of CPT-11. Cancer Res 51:4187–4191

    PubMed  CAS  Google Scholar 

  27. Kellis JT Jr, Vickery LE (1984) Inhibition of human estrogen synthetase (aromatase) by flavones. Science 225:1032–1034

    Article  PubMed  CAS  Google Scholar 

  28. Lampe JW, Bigler J, Horner NK, Potter JD (1999) UDP-glucuronosyltransferase (UGT1A1*28 and UGT1A6*2) polymorphisms in Caucasians and Asians: relationships to serum bilirubin concentrations. Pharmacogenetics 9:341–349

    Article  PubMed  CAS  Google Scholar 

  29. Lenfers BH, Loeffler TM, Droege CM, Hausamen TU (1999) Substantial activity of budesonide in patients with irinotecan (CPT-11) and 5-fluorouracil induced diarrhea and failure of loperamide treatment. Ann Oncol 10:1251–1253

    Article  PubMed  CAS  Google Scholar 

  30. Michael M, Brittain M, Nagai J et al (2004) A phase II study of activated charcoal to prevent irinotecan (CPT-11) Induced Diarrhea. In: Proc Am Soc Clin Oncol, San Franciso, CA

  31. Monaghan G, Ryan M, Seddon R et al (1996) Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert’s syndrome. Lancet 347:578–581

    Article  PubMed  CAS  Google Scholar 

  32. Ritter JK, Kessler FK, Thompson MT et al (1999) Expression and inducibility of the human bilirubin UDP-glucuronosyltransferase UGT1A1 in liver and cultured primary hepatocytes: evidence for both genetic and environmental influences. Hepatology 30:476–484

    Article  PubMed  CAS  Google Scholar 

  33. Rivory LP, Haaz MC, Canal P et al (1997) Pharmacokinetic interrelationships of irinotecan (CPT-11) and its three major plasma metabolites in patients enrolled in phase I/II trials. Clin Cancer Res 3:1261–1266

    PubMed  CAS  Google Scholar 

  34. Rivory LP, Robert J (1994) Reversed-phase high-performance liquid chromatographic method for the simultaneous quantitation of the carboxylate and lactone forms of the camptothecin derivative irinotecan, CPT-11, and its metabolite SN-38 in plasma. J Chromatogr B Biomed Appl 661:133–141

    Article  PubMed  CAS  Google Scholar 

  35. Rothenberg ML, Meropol NJ, Poplin EA et al (2001) Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel. J Clin Oncol 19:3801–3807

    PubMed  CAS  Google Scholar 

  36. Rougier P, Bugat R, Douillard JY et al (1997) Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 15:251–260

    PubMed  CAS  Google Scholar 

  37. Satoh T, Hosokawa M, Atsumi R et al (1994) Metabolic activation of CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin, a novel antitumor agent, by carboxylesterase. Biol Pharm Bull 17:662–664

    PubMed  CAS  Google Scholar 

  38. Takasuna K, Hagiwara T, Hirohashi M et al (1998) Inhibition of intestinal microflora beta-glucuronidase modifies the distribution of the active metabolite of the antitumor agent, irinotecan hydrochloride (CPT-11) in rats. Cancer Chemother Pharmacol 42:280–286

    Article  PubMed  CAS  Google Scholar 

  39. Takasuna K, Kasai Y, Kitano Y et al (1995) Protective effects of kampo medicines and baicalin against intestinal toxicity of a new anticancer camptothecin derivative, irinotecan hydrochloride (CPT-11), in rats. Jpn J Cancer Res 86:978–984

    PubMed  CAS  Google Scholar 

  40. Walgren RA, Walle UK, Walle T (1998) Transport of quercetin and its glucosides across human intestinal epithelial Caco-2 cells. Biochem Pharmacol 55:1721–1727

    Article  PubMed  CAS  Google Scholar 

  41. Walle T, Otake Y, Brubaker JA et al (2001) Disposition and metabolism of the flavonoid chrysin in normal volunteers. Br J Clin Pharmacol 51:143–146

    Article  PubMed  CAS  Google Scholar 

  42. Walle T, Otake Y, Galijatovic A et al (2000) Induction of UDP-glucuronosyltransferase UGT1A1 by the flavonoid chrysin in the human hepatoma cell line hep G2. Drug Metab Dispos 28:1077–1082

    PubMed  CAS  Google Scholar 

  43. Walle UK, Galijatovic A, Walle T (1999) Transport of the flavonoid chrysin and its conjugated metabolites by the human intestinal cell line Caco-2. Biochem Pharmacol 58:431–438

    Article  PubMed  CAS  Google Scholar 

  44. Zidan J, Haim N, Beny A et al (2001) Octreotide in the treatment of severe chemotherapy-induced diarrhea. Ann Oncol 12:227–229

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Sydney, Sydney, NSW, 2006, Australia

    Peter J. Tobin

  2. Sydney Cancer Centre, Royal Prince Alfred Hospital, Sydney, NSW, 2006, Australia

    Philip Beale, Leesa Noney, Sandy Liddell, Laurent P. Rivory & Stephen Clarke

  3. Department of Oncology, Concord Hospital, Concord, NSW, 2139, Australia

    Stephen Clarke

Authors
  1. Peter J. Tobin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Philip Beale
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Leesa Noney
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sandy Liddell
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Laurent P. Rivory
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Stephen Clarke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephen Clarke.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tobin, P.J., Beale, P., Noney, L. et al. A pilot study on the safety of combining chrysin, a non-absorbable inducer of UGT1A1, and irinotecan (CPT-11) to treat metastatic colorectal cancer. Cancer Chemother Pharmacol 57, 309–316 (2006). https://doi.org/10.1007/s00280-005-0053-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-005-0053-0

Keywords

Search

Navigation