LOSS OF DEOXYCYTIDINE KINASE EXPRESSION AND TETRAPLOIDIZATION OF HL-60 CELLS FOLLOWING LONG-TERM CULTURE IN 1,25-DIHYDROXYVITAMIN D-3

Development of drug resistance is a major problem in attempts to contr ol the growth of neoplastic cell populations. The resistance can be ei ther inherent or acquired by an exposure to a chemotherapeutic drug. T he available models for study of these phenomena have not led to major improvements in the therapy for human cancers. Therefore, in order to develop a new model for such studies, we have exposed human myeloid l eukemia cells HL60 to increasing concentrations of 1,25-dihydroxyvitam in D-3 (1,25D(3)) and characterized the emerging new phenotypes of the se cells over a period of 4 years. During the stepwise development of resistance only cells which did not adhere to the flask walls were pas saged. Beginning at 30 nM 1,25D(3) the sublines became resistant to th e differentiation-inducing and growth-retarding properties of 1,25D(3) even at 400 nM. Also, their growth rates in 1,25D(3)-free media incre ased. In addition, beginning at 40 nM 1,25D(3) the sublines acquired r esistance to 5-beta-D-arabinocytosine (araC) due to the lack of expres sion of the deoxycytidine kinase gene. The araC-resistant sublines wer e also near-tetraploid, as judged by their DNA content. When grown in 1,25D(3)-free long-term culture the phenotype was essentially stable. The development of cross-resistance to araC during growth in the prese nce of an unrelated compound (i.e., 1,25D(3)) shows that in some insta nces an apparently inherent drug resistance may in fact be due to a me tabolic defect resulting from an exposure to another agent. (C) 1996 A cademic Press, Inc.