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| Dynamics of chronic myeloid leukaemia |
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| Author(s): Michor F, Hughes TP, Iwasa Y, Branford S, Shah NP, Sawyers CL, Nowak MA |
| Source: NATURE Volume: 435 Issue: 7046 Pages: 1267-1270 Published: JUN 30 2005 |
| Times Cited: 192 References: 27 |
| Abstract: The clinical success of the ABL tyrosine kinase inhibitor imatinib in chronic myeloid leukaemia (CML) serves as a model for molecularly targeted therapy of cancer(1-4), but at least two critical questions remain. Can imatinib eradicate leukaemic stem cells? What are the dynamics of relapse due to imatinib resistance, which is caused by mutations in the ABL kinase domain? The precise understanding of how imatinib exerts its therapeutic effect in CML and the ability to measure disease burden by quantitative polymerase chain reaction provide an opportunity to develop a mathematical approach. We find that a four-compartment model, based on the known biology of haematopoietic differentiation(5), can explain the kinetics of the molecular response to imatinib in a 169-patient data set. Successful therapy leads to a biphasic exponential decline of leukaemic cells. The first slope of 0.05 per day represents the turnover rate of differentiated leukaemic cells, while the second slope of 0.008 per day represents the turnover rate of leukaemic progenitors. The model suggests that imatinib is a potent inhibitor of the production of differentiated leukaemic cells, but does not deplete leukaemic stem cells. We calculate the probability of developing imatinib resistance mutations and estimate the time until detection of resistance. Our model provides the first quantitative insights into the in vivo kinetics of a human cancer. |
| Document Type: Article |
| Language: English |
| Reprint Address: Michor, F (reprint author), Harvard Univ, Dept Math, Dept Organism & Evolutionary Biol, Program Evolutionary Dynam, Cambridge, MA 02138 USA |
Addresses:
1. Harvard Univ, Dept Math, Dept Organism & Evolutionary Biol, Program Evolutionary Dynam, Cambridge, MA 02138 USA
2. Inst Med & Vet Sci, Adelaide, SA 5000 Australia
3. Kyushu Univ, Dept Biol, Fukuoka 8128581, Japan
4. Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA
5. Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Dept Med & Mol Pharmacol,Dept Urol,Mol Biol Inst, Los Angeles, CA 90095 USA |
| Publisher: NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND |
| Subject Category: Multidisciplinary Sciences |
| IDS Number: 940JJ |
| ISSN: 0028-0836 |
| DOI: 10.1038/nature03669 |
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