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

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A pharmacodynamic study of 5-azacytidine in the P39 cell line. / Khan, Rasheed; Aggerholm, Anni; Hokland, Peter; Hassan, Moustapha; Hellstrom-Lindberg, Eva.

In: Experimental Hematology, Vol. 34, No. 1, 2006, p. 35-43.

Research output: Contribution to journalArticle

Harvard

Khan, R, Aggerholm, A, Hokland, P, Hassan, M & Hellstrom-Lindberg, E 2006, 'A pharmacodynamic study of 5-azacytidine in the P39 cell line', Experimental Hematology, vol. 34, no. 1, pp. 35-43. https://doi.org/10.1016/j.exphem.2005.09.007

APA

Khan, R., Aggerholm, A., Hokland, P., Hassan, M., & Hellstrom-Lindberg, E. (2006). A pharmacodynamic study of 5-azacytidine in the P39 cell line. Experimental Hematology, 34(1), 35-43. https://doi.org/10.1016/j.exphem.2005.09.007

CBE

Khan R, Aggerholm A, Hokland P, Hassan M, Hellstrom-Lindberg E. 2006. A pharmacodynamic study of 5-azacytidine in the P39 cell line. Experimental Hematology. 34(1):35-43. https://doi.org/10.1016/j.exphem.2005.09.007

MLA

Vancouver

Khan R, Aggerholm A, Hokland P, Hassan M, Hellstrom-Lindberg E. A pharmacodynamic study of 5-azacytidine in the P39 cell line. Experimental Hematology. 2006;34(1):35-43. https://doi.org/10.1016/j.exphem.2005.09.007

Author

Khan, Rasheed ; Aggerholm, Anni ; Hokland, Peter ; Hassan, Moustapha ; Hellstrom-Lindberg, Eva. / A pharmacodynamic study of 5-azacytidine in the P39 cell line. In: Experimental Hematology. 2006 ; Vol. 34, No. 1. pp. 35-43.

RIS

TY - JOUR

T1 - A pharmacodynamic study of 5-azacytidine in the P39 cell line

AU - Khan, Rasheed

AU - Aggerholm, Anni

AU - Hokland, Peter

AU - Hassan, Moustapha

AU - Hellstrom-Lindberg, Eva

N1 - The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Experimental Clinical Chemistry (013016010)

PY - 2006

Y1 - 2006

N2 - 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.

AB - 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.

U2 - 10.1016/j.exphem.2005.09.007

DO - 10.1016/j.exphem.2005.09.007

M3 - Article

C2 - 16413389

VL - 34

SP - 35

EP - 43

JO - Experimental Hematology

JF - Experimental Hematology

SN - 1873-2399

IS - 1

ER -