title: Theoretical analysis of conjugate localization in two-step cancer chemotherapy.
abstract: Considerable research has been aimed at improving the efficacy of chemotherapeutic agents for cancer therapy. A promising two-step approach that is designed to minimize systemic drug toxicity while maximizing activity in tumors employs monoclonal antibody-enzyme conjugates for the activation of anti-cancer prodrugs. A mathematical model based on the biology of human 3677 melanoma xenografts in nude mice is presented, analyzed, and numerically simulated to study the biodistribution, pharmacokinetics, and intratumoral localization properties of L49-beta-lactamase fusion proteins in solid tumor masses. The model predictions were compared with published experimental data and an excellent correlation was found to exist. Analytic expressions for the total concentration of conjugate in the tumor, the time at which the concentration is maximal, and the half life of conjugate in the tissue were derived. From these results, key parameters were isolated; and the effects of the tumor vasculature, binding kinetics, and administration schedule were investigated. The antibody-antigen dissociation ratio, the conjugate permeability, and the inter-capillary half distance within the tumor mass were found to strongly influence localization and retention in the tumor. The model was used to examine various dosing strategies in an attempt to determine which regimen would provide the best biodistribution results. The results of administering a uniform dose of conjugate via bolus injection, multiple injections, and continuous infusion were compared. The model predicts that when saturation of binding sites does not occur, dosing strategy has little effect on the amount of conjugate that localizes in the tumor.
authors.affiliation: Department of Applied Mathematics, University of Washington, Box 352420, Seattle WA 98195-2420, USA. tjackson@ima.umn.edu
authors.forename: T L
authors.initials: TL
authors.lastname: Jackson
authors.forename: S R
authors.initials: SR
authors.lastname: Lubkin
authors.forename: J D
authors.initials: JD
authors.lastname: Murray
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003198:Computer Simulation; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009716:Numerical Analysis, Computer-Assisted; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014183:Transplantation, Heterologous; D001618:beta-Lactamases / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D011355:Prodrugs; D011993:Recombinant Fusion Proteins; D001618:beta-Lactamases