Overcoming resistance and pharmacologicaly-directed tailor-made chemotherapy for leukemia

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To establish pharmacologicaly-directed tailor-made chemotherapy for leukemia, the mechanisms of action and resistance of clofarabine were investigated using two newly developed clofarabine-resistant leukemic cell lines.The resistant cell lines exhibited reduced clofarabine triphosphate production due to decreased mRNA levels of 3 cell membrane transporters and low protein levels of 2 kinases. The cell lines also showed increased Bcl-2 protein levels, suggestive of antiapoptosis. A cytarabine-resisntant leukemic cell line that had been previously develped showed reduction in only one transporter and one kinase, and 1/10 reduced cytarabine triphosphate. This cell line still possessed the sensitivity to clofarabine, which was atttibutable to the capacity to produce clofarabine triphosphate.Thus, pharmacologically-directed tailor-made chemotherapy will be established using surrogate markers (intracellular triphosphate production and Bcl-2 exression) to overcome resistance of leukemia.