scheduling chemotherapy catch 22 between cell kill and resistance evolution调度化疗赶上22细胞杀死和电阻之间的进化.pdf

Journcrl of Theo,rricoi Medicme. Vol 2, pp. 215-232 g2000 OPA ( O ~ e r s r a sPubl~sher,Assoc~atlon)N.V. Repnnts available directly from the publisher Published by licence under Photocopying permitted by licenze only the Gordun dnd Breach Science Publ~shersimprint Prlnred in Malaysiii. Scheduling Chemotherapy: Catch 22 between Cell Kill and Resistance Evolution SHEA N. GARDNER* NERC Centre jor Populatron Brologj, Imper~ulCollege at Sduood Park, Arcor, Berkrhwe SL5 7PY UK (Recerved 1 June 1999; Injinal form 6 October 1999) Dose response curves show that prolonged drug exposure at a low concentration may kill more cells than short exposures at higher drug concentrations, particularly for cell cycle phase specific drugs. Applying drugs at low concentrations for prolonged periods, however, allows cells with partial resistance to evolve higher levels of resistance through stepwise processes such as gene amplification. Models are developed for cell cycle specific (CS) and cell cycle nonspecific (CNS) drugs to identify the schedule of drug application