title: Distribution and quantification of irinotecan and its active metabolite SN-38 in colon cancer murine model systems using MALDI MSI.
abstract: Tissue distribution and quantitative analysis of small molecules is a key to assess the mechanism of drug action and evaluate treatment efficacy. The prodrug irinotecan (CPT-11) is widely used for chemotherapeutic treatment of colorectal cancer. CPT-11 requires conversion into its active metabolite SN-38 to exert the desired pharmacological effect. MALDI-Fourier transform ion cyclotron resonance (FT-ICR) and MALDI-time-of-flight (TOF) mass spectrometry imaging (MSI) were performed for detection of CPT-11 and SN-38 in tissue sections from mice post CPT-11 injection. In-depth information was gained about the distribution and quantity of drug compounds in normal and tumor tissue. The prodrug was metabolized, as proven by the detection of SN-38 in liver, kidney and digestive tract. In tumors from genetic mouse models for colorectal cancer (Apc (1638N/wt) x pvillin-Kras (V12G) ), CPT-11 was detected but not the active metabolite. In order to correlate drug distribution relative to vascularization, MALDI data were superimposed with CD31 (PECAM-1) immunohistochemistry. This analysis indicated that intratumoral access of CPT-11 mainly occurred by extravasation from microvessels. The present study exploits the power of MALDI MSI in drug analysis, and presents a novel approach to monitor drug distribution in relation to vessel functionality in preclinical and clinical research.
authors.affiliation: Research Unit Analytical Pathology, Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Buck
authors.forename: Susanne
authors.initials: S
authors.lastname: Halbritter
authors.forename: Christoph
authors.initials: C
authors.lastname: Späth
authors.forename: Annette
authors.initials: A
authors.lastname: Feuchtinger
authors.forename: Michaela
authors.initials: M
authors.lastname: Aichler
authors.forename: Horst
authors.initials: H
authors.lastname: Zitzelsberger
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Janssen
authors.forename: Axel
authors.initials: A
authors.lastname: Walch
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000032:analysis / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism / Q000493:pharmacokinetics; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D016903:Drug Monitoring / Q000295:instrumentation / Q000379:methods*; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000295:instrumentation / Q000379:methods*; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D000077146:Irinotecan; D002166:Camptothecin