Advanced

A pharmacodynamic study of 5-azacytidine in the P39 cell line

Khan, Rasheed LU ; Aggerholm, Anni; Hokland, Peter; Hassan, Moustapha and Hellstrom-Lindberg, Eva (2006) In Experimental Hematology 34(1). p.35-43
Abstract
OBJECTIVE: 5-azacytidine (azacytidine), a DNA hypomethylating agent, was recently approved as the first therapeutic agent for the treatment of myelodysplastic syndromes. The present subcutaneous dosing schedule, 75 mg/m(2) for 7/28 days, is based on early clinical studies and may constitute a practical problem for patients. The present in vitro study aimed at evaluating the pharmacodynamics of azacytidine, thereby providing a rationale for clinical dose-finding studies. METHODS: P39 cells were incubated with 0.1, 0.5, and 1 microM azacytidine daily for 24, 48, and 72 hours, followed by 48 hours in drug-free medium. The effects of azacytidine on cell growth, proliferation, apoptosis, cell cycle status, and promoter methylation of... (More)
OBJECTIVE: 5-azacytidine (azacytidine), a DNA hypomethylating agent, was recently approved as the first therapeutic agent for the treatment of myelodysplastic syndromes. The present subcutaneous dosing schedule, 75 mg/m(2) for 7/28 days, is based on early clinical studies and may constitute a practical problem for patients. The present in vitro study aimed at evaluating the pharmacodynamics of azacytidine, thereby providing a rationale for clinical dose-finding studies. METHODS: P39 cells were incubated with 0.1, 0.5, and 1 microM azacytidine daily for 24, 48, and 72 hours, followed by 48 hours in drug-free medium. The effects of azacytidine on cell growth, proliferation, apoptosis, cell cycle status, and promoter methylation of E-cadherin, ER, and HIC genes were studied. RESULTS: Azacytidine decreased cell growth and proliferation, increased apoptosis, and affected cell cycle status in a dose-dependent manner. However, the exposure time, 24 to 72 hours, at doses between 0.5 and 1 microM, did not significantly affect any of these variables. Using first-order exponential pharmacokinetic model, we found that the effect of 1, 2, or 3 microM over 24 hours did not differ from that of 0.5 to 1 microM given over 48 to 72 hours. Induction of promoter hypomethylation was observed already after 24 hours of exposure with >or=0.5 microM azacytidine with no clear dose-effect relationship. CONCLUSION: Our results indicate that optimal cellular effects of azacytidine might be achieved by shorter exposure times. The model provides information about the relation between azacytidine dose intensity and exposure time on malignant myeloid cells, which could serve as a rationale for further clinical development of practical, safe, and cost-effective dosing schedules. (Less)
Please use this url to cite or link to this publication:
author
publishing date
type
Contribution to journal
publication status
published
subject
in
Experimental Hematology
volume
34
issue
1
pages
35 - 43
publisher
Elsevier
external identifiers
  • wos:000235133900006
  • scopus:30344472703
ISSN
1873-2399
DOI
10.1016/j.exphem.2005.09.007
language
English
LU publication?
no
id
f6d56d2d-4539-4716-8e63-622a3db844ea (old id 1298370)
date added to LUP
2009-07-10 11:46:25
date last changed
2017-01-01 07:56:17
@article{f6d56d2d-4539-4716-8e63-622a3db844ea,
  abstract     = {OBJECTIVE: 5-azacytidine (azacytidine), a DNA hypomethylating agent, was recently approved as the first therapeutic agent for the treatment of myelodysplastic syndromes. The present subcutaneous dosing schedule, 75 mg/m(2) for 7/28 days, is based on early clinical studies and may constitute a practical problem for patients. The present in vitro study aimed at evaluating the pharmacodynamics of azacytidine, thereby providing a rationale for clinical dose-finding studies. METHODS: P39 cells were incubated with 0.1, 0.5, and 1 microM azacytidine daily for 24, 48, and 72 hours, followed by 48 hours in drug-free medium. The effects of azacytidine on cell growth, proliferation, apoptosis, cell cycle status, and promoter methylation of E-cadherin, ER, and HIC genes were studied. RESULTS: Azacytidine decreased cell growth and proliferation, increased apoptosis, and affected cell cycle status in a dose-dependent manner. However, the exposure time, 24 to 72 hours, at doses between 0.5 and 1 microM, did not significantly affect any of these variables. Using first-order exponential pharmacokinetic model, we found that the effect of 1, 2, or 3 microM over 24 hours did not differ from that of 0.5 to 1 microM given over 48 to 72 hours. Induction of promoter hypomethylation was observed already after 24 hours of exposure with >or=0.5 microM azacytidine with no clear dose-effect relationship. CONCLUSION: Our results indicate that optimal cellular effects of azacytidine might be achieved by shorter exposure times. The model provides information about the relation between azacytidine dose intensity and exposure time on malignant myeloid cells, which could serve as a rationale for further clinical development of practical, safe, and cost-effective dosing schedules.},
  author       = {Khan, Rasheed and Aggerholm, Anni and Hokland, Peter and Hassan, Moustapha and Hellstrom-Lindberg, Eva},
  issn         = {1873-2399},
  language     = {eng},
  number       = {1},
  pages        = {35--43},
  publisher    = {Elsevier},
  series       = {Experimental Hematology},
  title        = {A pharmacodynamic study of 5-azacytidine in the P39 cell line},
  url          = {http://dx.doi.org/10.1016/j.exphem.2005.09.007},
  volume       = {34},
  year         = {2006},
}