title: Encapsulation of mitomycin C in albumin microspheres markedly alters pharmacokinetics, drug quinone reduction in tumour tissue and antitumour activity. Implications for the drugs' in vivo mechanism of action.
abstract: Pharmacokinetics and metabolism of mitomycin C (MMC) have been studied in NMRI mice bearing MAC 16 colon adenocarcinoma after direct intratumoural injection of either 500 micrograms free MMC or the same dose incorporated in albumin microspheres. Microspheres produced a tumour pharmacokinetic profile of steady state drug levels, avoiding the much higher early peak (20.5 micrograms/tumour vs 98.9 micrograms/tumour) and lower trough of free MMC, and reducing significantly the levels of drug reaching the systemic circulation (AUC 1.8 micrograms/mL x hr for microspheres vs 6.8 micrograms/mL x hr for free drug). 2,7-Diaminomitosene (2,7-DM), a key intermediate in MMC quinone bioreduction, was used as an indicator of drug metabolic activation in tumour tissue. Peak levels were 10-fold higher (11.2 micrograms/tumour vs 1.1 micrograms/tumour) and area under the curve 5-fold higher after free drug. Even taking into account differences in tumour pharmacokinetic profiles of the parent drug, microspheres actively inhibited 2,7-DM formation 3-fold. However, the microspheres generated a completely different pattern of drug metabolism where four previously uncharacterized mitosane metabolites and elevated levels of cis and trans 1-hydroxy 2,7-diaminomitosene were detected. Despite similar parent drug exposure in tumours, free drug was significantly more active (P < 0.05, Student's t-test) against MAC 16. These results suggest that formation of 2,7-DM correlates more closely with antitumour activity than sustained parent drug levels or appearance of other key metabolites. Potentially, they provide the first direct evidence for an in vivo mechanism of action dependent on bioreductive activation and formation of 2,7-DM.
authors.affiliation: Imperial Cancer Research Fund, Medical Oncology Unit, Western General Hospital, Edinburgh, U.K.
authors.forename: J
authors.initials: J
authors.lastname: Cummings
authors.forename: L
authors.initials: L
authors.lastname: Allan
authors.forename: J F
authors.initials: JF
authors.lastname: Smyth
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism; D000418:Albumins; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001711:Biotransformation; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D004337:Drug Carriers; D004339:Drug Compounding / Q000379:methods; D051379:Mice; D008815:Mice, Inbred Strains; D008863:Microspheres; D016685:Mitomycin / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D008937:Mitomycins / Q000032:analysis; D010084:Oxidation-Reduction
chemical_list: D000418:Albumins; D000970:Antineoplastic Agents; D004337:Drug Carriers; D008937:Mitomycins; D016685:Mitomycin; C056707:2,7-diaminomitosene