Cancer treatment by telomerase inhibitors: predictions by a kinetic model.
The inhibition of telomerase activity in actively dividing cells leads to shortening of their telomeres and suppression of cell growth when the telomere lengths become smaller than a certain threshold value (typically about 1-2 kb of DNA). We evaluated the time (efficacy delay) required to reach the threshold telomeric DNA size after initiation of treatment, which is of critical importance for the efficacy of telomerase inhibitors. A model based on the solution of a system of differential equations was developed to analyze the efficacy delay and dynamics of tumor growth. The efficacy delay was strongly dependent on the size distribution of telomere lengths at the treatment initiation. An increase in the heterogeneity of telomere size resulted in shortening of the delay. However, the long-term dynamics of tumors with homogeneous populations of telomeres were more significantly affected by telomerase inhibitors compared to tumors with heterogeneous size distribution of telomeres. Size distribution of telomeres and tumor doubling times are of critical importance for the dynamics of tumor growth in presence of telomerase inhibitors.
Sidorov
Igor A
IA
National Cancer Institute, NCI-Frederick, NIH, PO Box B, Frederick, MD 21702-1201, USA. sidorovi@ncifcrf.gov
Hirsch
Ken S
KS
Harley
Calvin B
CB
Dimitrov
Dimiter S
DS
D002455:Cell Division / Q000187:drug effects; D003198:Computer Simulation; D005544:Forecasting; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors
D019098:Telomerase