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


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/m(2) 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.
Tobin
Peter J
PJ
Department of Pharmacology, University of Sydney, NSW, Australia.
Beale
Philip
P
Noney
Leesa
L
Liddell
Sandy
S
Rivory
Laurent P
LP
Clarke
Stephen
S
D000284:Administration, Oral; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D018938:Caco-2 Cells; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced; D004334:Drug Administration Schedule; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage / Q000009:adverse effects; D005965:Glucuronates / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007275:Injections, Intravenous; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009503:Neutropenia / Q000139:chemically induced; D010865:Pilot Projects
C114685:7-ethyl-10-hydroxycamptothecin beta-glucuronide; D005419:Flavonoids; D005965:Glucuronates; C043561:chrysin; D000077146:Irinotecan; D014453:Glucuronosyltransferase; D002166:Camptothecin