Cholinergic toxic syndrome by the anticancer drug irinotecan: Acetylcholinesterase does not play a major role

Abstract

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.

Inhibition of acetylcholinesterase in patients receiving irinotecan (camptothecin-11)

“…Irinotecan was a potent inhibitor of acetylcholinesterase in each of the erythrocyte acetylcholinesterase preparations (mean 50% inhibitory concentration [IC 50 ], 0.3 ± 0.1 μmol/L) (Table I). There was remarkably little interindividual difference in the sensitivity of acetylcholinesterase to irinotecan, which may have explained the differences in results obtained by Blandizzi et al , 3 Dodds and Rivory, 2 and Morton et al 1 . Dodds and Rivory and Morton et al observed IC 50 values of approximately 0.3 μmol/L for irinotecan, as opposed to only 20% inhibition of acetylcholinesterase activity at 100 μmol/L irinotecan reported by Blandizzi et al In our study there was only a 2‐fold difference in individual acetylcholinesterase sensitivity to irinotecan, with a mean IC 50 of 0.3 ± 0.1 μmol/L (N = 18), which is consistent with the findings of Dodds and Rivory and Morton et al The remarkably constant IC 50 value suggests that irinotecan‐induced cholinergic toxicity is unlikely to be affected by interindividual pharmacogenetic differences.…”

“…The study was undertaken at Royal Prince Alfred Hospital in Sydney, Australia, and was approved by the Ethics Committee of that institution. Morton et al 1 and Dodds and Rivory 2 provided evidence that this syndrome is a result of the inhibition of acetylcholinesterase by irinotecan; however, Blandizzi et al 3 have recently reported observing much less potent inhibition by irinotecan in patients. Our study measured the extent of inhibition of human erythrocyte acetylcholinesterase in 18 patient preparations.…”

“…To help explain some of the discrepancies between different research groups, we examined whether any of the previously conducted studies may have had confounding factors that biased their results. For example, in the study by Blandizzi et al , 3 the inhibition of acetylcholinesterase by irinotecan was studied in the presence of 30 μmol/L quinidine, which was used to inhibit serum cholinesterase. Although quinidine itself is not an inhibitor of acetylcholinesterase, it may possibly have altered the extent of inhibition of acetylcholinesterase by irinotecan.…”

“…Another possibility we considered to explain why Blandizzi et al 3 did not observe considerable inhibition of acetylcholinesterase by irinotecan was that the concentration of the substrate acetylthiocholine iodide was too high. Blandizzi et al reported using 0.075 mol/L acetylthiocholine iodide to examine irinotecan inhibition of acetylcholinesterase, which is approximately 900 times the Michaelis‐Menten constant (K m ), as determined by this study.…”

The Crystal Structure of the Complex of the Anticancer Prodrug 7-Ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11) with Torpedo californica Acetylcholinesterase Provides a Molecular Explanation for Its Cholinergic Action

“…However, recent studies (Blandizzi et al, 2001(Blandizzi et al, , 2002 have suggested that this may not be caused by a direct interaction of the drug with the enzyme. To elucidate the interaction of CPT-11 with AChE, we have performed detailed biochemical studies with the drug and with several analogs using three AChEs.…”