Fasting protects against the side effects of irinotecan treatment but does not affect anti-tumour activity in mice.
BACKGROUND
The main limitation to the use of irinotecan in the treatment of colorectal cancer is the severity of side effects, including neutropaenia and diarrhoea. Here, we explored the effects of 3 days of fasting on irinotecan-induced toxicities, on plasma, liver and tumour pharmacokinetics and on anti-tumour activity in mice.


METHODS
Male BALB/c mice received C26 colon carcinoma cells subcutaneously. They were randomized 1:1 into equally sized ad libitum fed and fasted groups after which they were treated with irinotecan. Weight and adverse side effects were recorded daily. At the end of the experiment, tumours were resected and weighed, and concentrations of irinotecan and its active metabolite SN-38 were determined in plasma and tumour.


RESULTS
Fasting prevented the diarrhoea and visible signs of discomfort induced by irinotecan. Ad libitum fed animals developed leucopenia compared with untreated controls, whereas fasted mice did not. Irinotecan suppressed tumour growth equally in both treated groups, compared with untreated controls. Levels of the active irinotecan metabolite SN-38 9 (calculated as AUC values) were significantly lower in fasted mice in both plasma and liver, but not in tumour tissue.


CONCLUSIONS
Fasting protected against irinotecan-induced side effects without interfering with its anti-tumour efficacy. Fasting induced a lower systemic exposure to SN-38, which may explain the absence of adverse side effects, while tumour levels of SN-38 remained unchanged. These data offer important new approaches to improve treatment with irinotecan in patients.
Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.
Sander A
SA
Huisman
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
Peter
P
de Bruijn
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
Inge M
IM
Ghobadi Moghaddam-Helmantel
Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.
Jan N M
JN
IJzermans
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
Erik A C
EA
Wiemer
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
Ron H J
RH
Mathijssen
Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.
Ron W F
RW
de Bruin
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000235:genetics; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003967:Diarrhea / Q000517:prevention & control; D005215:Fasting; D020719:Glucuronides / Q000097:blood; D000077146:Irinotecan; D007970:Leukopenia / Q000517:prevention & control; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000378:metabolism; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D015431:Weight Loss / Q000187:drug effects
C441475:7-ethyl-10-hydroxycamptothecin glucuronide; D000972:Antineoplastic Agents, Phytogenic; D020719:Glucuronides; D012333:RNA, Messenger; D000077146:Irinotecan; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase; C500145:Ces2c protein, mouse; D002166:Camptothecin