Cholinergic toxic syndrome by the anticancer drug irinotecan: acetylcholinesterase does not play a major role.
BACKGROUND
The anticancer drug irinotecan induces cholinergic side effects that are currently ascribed to the blockade of acetylcholinesterase. This study investigated (1) the pattern of acetylcholinesterase activity in patients receiving treatment with irinotecan and (2) the relationship between acetylcholinesterase activity and plasma concentrations of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), and SN-38 glucuronide (SN-38G).


METHODS
Twenty-five patients with advanced colorectal cancer were treated with 250 mg/m(2) irinotecan administered by intravenous infusion for 60 minutes. Blood samples were collected before drug infusion and at 15 minutes and 45 minutes after the start of drug infusion. Blood acetylcholinesterase activity was determined by a colorimetric enzymatic assay, and irinotecan, SN-38, and SN-38G concentrations were determined in plasma by HPLC. The in vitro effects of irinotecan and other drugs on human acetylcholinesterase were also assessed.


RESULTS
Compared with basal values, the activity of acetylcholinesterase in blood specimens collected during irinotecan infusion at 15 minutes (-0.76%) and at 45 minutes (-1.50%) showed no changes. No relationships were established between the activity of blood acetylcholinesterase at 15 or 45 minutes and plasma concentrations of irinotecan, SN-38, or SN-38G measured at the same time points. In vitro, the activity of acetylcholinesterase was inhibited by 100-micromol/L irinotecan (-24.8%) and markedly reduced by 1-micromol/L physostigmine (-86.7%), whereas neither SN-38 nor camptothecin had an effect.


CONCLUSIONS
Although the use of erythrocyte acetylcholinesterase as a surrogate marker of acetylcholinesterase activity in the nervous system has not been firmly established, our findings do not support the hypothesis that the toxic cholinergic syndrome associated with irinotecan treatment depends on acetylcholinesterase blockade.
Blandizzi
Corrado
C
Interdepartmental Center for Research in Clinical Pharmacology and Experimental Therapeutics, University of Pisa, Italy.
Danesi
Romano
R
De Paolis
Barbara
B
Di Paolo
Antonello
A
Colucci
Rocchina
R
Falcone
Alfredo
A
Del Tacca
Mario
M
D000110:Acetylcholinesterase / Q000097:blood / Q000502:physiology*; D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy; D000368:Aged; D000704:Analysis of Variance; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D002166:Camptothecin / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000097:blood / Q000627:therapeutic use; D018678:Cholinergic Agents / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D002800:Cholinesterase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy; D016001:Confidence Intervals; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D010830:Physostigmine / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D018678:Cholinergic Agents; D002800:Cholinesterase Inhibitors; D000077146:Irinotecan; D010830:Physostigmine; D000110:Acetylcholinesterase; D002166:Camptothecin