title: A mathematical model of the impact of infused targeted cytotoxic agents on brain tumours: implications for detection, design and delivery.
abstract: Motivated by the recent development of highly specific agents for brain tumours, we develop a mathematical model of the spatio-temporal dynamics of a brain tumour that receives an infusion of a highly specific cytotoxic agent (e.g. IL-4-PE, a cytotoxin comprised of IL-4 and a mutated form of Pseudomonas exotoxin). We derive an approximate but accurate mathematical formula for the tumour cure probability in terms of the tumour characteristics (size at time of detection, proliferation rate, diffusion coefficient), drug design (killing rate, loss rate and convection constants for tumour and tissue), and drug delivery (infusion rate, infusion duration). Our results suggest that high specificity is necessary but not sufficient to cure malignant gliomas; a nondispersed spatial profile of pretreatment tumour cells and/or good drug penetration are also required. The most important levers to improve tumour cure appear to be earlier detection, higher infusion rate, lower drug clearance rate and better convection into tumour, but not tissue. In contrast, the tumour cure probability is less sensitive to a longer infusion duration and enhancements in drug potency and drug specificity.
authors.affiliation: Sloan School of Management, MIT, Cambridge, MA 02142-1347, USA. lwein@mit.edu
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Wein
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Wu
authors.forename: Alexandra G
authors.initials: AG
authors.lastname: Ianculescu
authors.forename: Raj K
authors.initials: RK
authors.lastname: Puri
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000633:toxicity; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods*; D015195:Drug Design; D005098:Exotoxins / Q000008:administration & dosage* / Q000633:toxicity; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D036502:Infusions, Intralesional; D015847:Interleukin-4 / Q000008:administration & dosage* / Q000633:toxicity; D008962:Models, Theoretical; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D005098:Exotoxins; C059989:IL-4-PE40 protein, recombinant; D011993:Recombinant Fusion Proteins; D015847:Interleukin-4