Cytosine β-D-Arabinofuranoside Drug Sensitivity in Down Syndrome Lymphoblastoid Cell Lines
Bartnik, Catherine Michelle
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Down syndrome (DS) is the result of improper chromosomal segregation known as nondisjunction culminating with the genetic aberration, trisomy 21. These individuals have an increased risk of developing leukemia with an even greater risk of developing acute myeloid leukemia (AML) at a young age. A remarkable feature of DS AML is the high event free survival (EFS) rate in comparison to non-DS AML individuals. It has been postulated that this positive prognosis is the result of a high-dose protocol utilizing the chemotherapeutic agent, cytosine 𝛽-D-arabinofuranoside (Ara-C). While previous studies have indicated a difference in Ara-C sensitivity among DS and non-DS leukemia (malignant) cells, the sensitivity of DS and non-malignant non-DS lymphoblastoid cells (LCLs) to Ara-C is not known and is an area of scientific interest. This study compares sensitivity to Ara-C in LCLs derived from DS individuals to those from individuals without DS. Using a small (n= 38) case-control cohort in which DS cells were matched to non-DS cells for both age and sex, no difference in sensitivity to Ara-C was seen as measured by percent survival of cells at various Ara-C concentrations and by IC50 and AVC values. However, analysis of the expanded cohort (n= 124) found DS LCLs to be significantly more sensitive to Ara-C at the 5 µM concentration, and with respect to IC50 value and AVC value. These results confirm the presence of a non-tumor genetic factor influencing drug sensitivity in DS individuals. The factor, if found, could greatly change the treatment of non-DS AML individuals.