title: Structural identification and biological activity of 7-methyl-10,11-ethylenedioxy-20(S)-camptothecin, a photodegradant of lurtotecan.
abstract: An additional chromatographic peak was observed in plasma samples of patients receiving NX 211, a liposomal formulation of the topoisomerase I inhibitor lurtotecan. We have isolated and purified this product by sequential solid-phase extractions, and we report its structure and cytotoxicity relative to lurtotecan and related agents. Nuclear magnetic resonance data indicate that cleavage of the piperazino moiety occurred at the N-C bond of the B-ring, yielding 7-methyl-10,11-ethylenedioxy-20(S)-camptothecin (MEC). Tests of the growth inhibition potential of MEC in seven human tumor cell lines showed that the compound was approximately 2-18-fold more cytotoxic than lurtotecan, topotecan, and 7-ethyl-10-hydroxy-20(S)-camptothecin (SN-38). Subsequently, we found that MEC was the product of rapid photolysis of lurtotecan, with the rate of degradation inversely proportional to NX 211 concentrations, and greatly depends on light intensity. Furthermore, MEC concentrations were found to increase significantly in plasma samples exposed to laboratory light but not in blood. MEC was not produced from NX 211 in the presence of human liver microsomes, suggesting that it is not a product of cytochrome P-450 metabolism. Using a validated analytical method, trace levels of MEC were quantitated in blood samples of two patients. These observations confirm that the precautions for protection from light currently specified for preparation and administration of NX 211 dose solutions are critical. Procedures to minimize formation of MEC, by the use of amber vials for NX 211 and by preparation of dilutions immediately before clinical use in a fashion completely protected from light, are now being routinely implemented.
authors.affiliation: Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, 3075 EA Rotterdam, The Netherlands. loos@pcnh.azr.nl
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Loos
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: Diederik F S
authors.initials: DF
authors.lastname: Kehrer
authors.forename: Peter
authors.initials: P
authors.lastname: de Bruijn
authors.forename: Franciscus M H
authors.initials: FM
authors.lastname: de Groot
authors.forename: Marta
authors.initials: M
authors.lastname: Hamilton
authors.forename: Kees
authors.initials: K
authors.lastname: Nooter
authors.forename: Gerrit
authors.initials: G
authors.lastname: Stoter
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000528:radiation effects*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology* / Q000528:radiation effects*; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D008027:Light; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: C458822:7-methyl-10,11-ethylenedioxy-20-camptothecin; D000970:Antineoplastic Agents; C091719:lurtotecan; D003577:Cytochrome P-450 Enzyme System; D002166:Camptothecin