Effect of dexamethasone on the antileukemic effect of cytarabine: role of deoxycytidine kinase.

Abstract

Dexamethasone (DEX) is often used in the initial treatment of leukemia. Earlier we demonstrated that DEX decreased the activity of deoxycytidine kinase (dCK) which is essential for the activation of cytarabine (ara-C). Therefore we investigated the effect of DEX on the in vivo sensitivity of acute myeloid leukemia (AML) to ara-C and another deoxycytidine analog, gemcitabine, in the Brown Norway Myeloid Leukemia (BNML) rat model for AML, and its ara-C resistant variant B-araC, in relation to the effects on dCK activity.The antileukemic effect was evaluated as survival of the rats, while dCK activity was measured in leukemic spleen (completely consisting of BNML cells) with liver as representative normal tissue, 24 hr after treatment with ara-C or DEX with radioactive deoxycytidine (CdR) as a substrate.Treatment with ara-C increased life-span of BNML by 200%, which was not affected by DEX. Gemcitabine was ineffective. In the liver of BNML bearing rats DEX decreased dCK activity 33%, while ara-C increased dCK activity slightly (to 129%), but in the combination of ara-C/DEX dCK activity was also decreased. In the livers of Bara-C bearing rats dCK was 2.7-fold higher compared to BNML rats, which was increased 179% in the gemcitabine-DEX treated rats. In BNML leukemic spleens DEX decreased dCK activity 41% and gem/dex 46%, but ara-C increased dCK activity to 123%, but in the combination this effect was neutralized. In Bara-C spleens only ara-C/dex decreased dCK activity (32%).In conclusion; in an AML rat model DEX did not affect the antileukemic effect of ara-C, nor the dCK activity.