Loss of deoxcytidine kinase expression and tetraploidization of HL60 cells following long-term culture in 1,25-dihydroxyvitamin D3.
Development of drug resistance is a major problem in attempts to control the growth of neoplastic cell populations. The resistance can he either inherent or acquired by an exposure to a chemotherapeutic drug. The 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 leukemia cells HL60 to increasing concentrations of 1,25-dihydroxyvitamin D3 (1,25D3) and characterized the emerging new phenotypes of these cells over a period of 4 years. During the stepwise development of resistance only cells which did not adhere to the flask walls were passaged. Beginning at 30 nM 1,25D3 the sublines became resistant to the differentiation-inducing and growth-retarding properties of 1,25D3 even at 400 nM. Also, their growth rates in 1,25D3-free media increased. In addition, beginning at 40 nM 1,25D3 the sublines acquired resistance to 5-beta-D-arabinocytosine (araC) due to the lack of expression of the deoxycytidine kinase gene. The araC-resistant sublines were also near-tetraploid, as judged by their DNA content. When grown in 1,25D3-free long-term culture the phenotype was essentially stable. The development of cross-resistance to araC during growth in the presence of an unrelated compound (i.e., 1,25D3) shows that in some instances an apparently inherent drug resistance may in fact he due to a metabolic defect resulting from an exposure to another agent.
Wajchmann
H J
HJ
Department of Pathology and Laboratory Medicine, UMD-New Jersey Medical School, Newark 07103, USA.
Rathod
B
B
Song
S
S
Xu
H
H
Wang
X
X
Uskokovic
M R
MR
Studzinski
G P
GP
D001345:Autoradiography; D015152:Blotting, Northern; D002117:Calcitriol / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002999:Clone Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D003470:Culture Media / Q000494:pharmacology*; D003561:Cytarabine / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000032:analysis / Q000187:drug effects; D003842:Deoxycytidine Kinase / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D011003:Ploidies; D012333:RNA, Messenger / Q000032:analysis / Q000187:drug effects; D013997:Time Factors
D003470:Culture Media; D004273:DNA, Neoplasm; D012333:RNA, Messenger; D003561:Cytarabine; D003842:Deoxycytidine Kinase; D002117:Calcitriol