title: Cloning and characterization of a human BCR/ABL-positive cell line, K562/RR, resistant to the farnesyltransferase inhibition by tipifarnib.
abstract: OBJECTIVE
  Results of previous studies have suggested that tipifarnib (Zarnestra), a farnesyltransferase inhibitor, is useful for treating various hematological disorders, including chronic myeloid leukemia. However, acquisition of resistance may be a problem for patients being treated with tipifarnib.
  
  
  METHODS
  We generated a tipifarnib-resistant BCR/ABL-positive cell line, K562/RR, and examined its characteristics.
  
  
  RESULTS
  While levels of cleaved caspase-3, cleaved caspase-7, cleaved caspase-9, and cleaved poly (ADP-ribose) polymerase were significantly increased in K562 cells, the levels were not changed in K562/RR cells with tipifarnib treatment, indicating that induction of apoptosis signaling mediated by tipifarnib is much less in K562/RR cells than in K562 cells. In addition, tipifarnib-mediated induction of cell-cycle blockage was abrogated in K562/RR cells. No mutation of farnesyltransferase alpha and beta genes was found and the level of unprocessed HDJ-2, which is a substrate of farnesyltransferase, was increased by tipifarnib treatment in K562/RR cells, suggesting that tipifarnib inhibits protein farnesylation in K562/RR cells in the same manner as in K562 cells and that mechanisms independent of farnesyltransferase activity are involved in the acquisition of resistance to tipifarnib in these cells. By DNA microarray analyses using a cDNA microarray comprising 25,000 genes, we identified 5 genes with higher expression levels in K562/RR cells than in K562 cells. These genes include beta-globin, calcium channel Caveolin 2, and FEN1, which is involved in DNA replication and repair, and CUGBP2, which may affect expression of cyclooxygenase 2.
  
  
  CONCLUSIONS
  The results of this study provide useful information for clarification of the mechanisms of resistance to tipifarnib.
authors.affiliation: Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Miyoshi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nagai
authors.forename: Satoru
authors.initials: S
authors.lastname: Kikuchi
authors.forename: Ken
authors.initials: K
authors.lastname: Ohmine
authors.forename: Makiko
authors.initials: M
authors.lastname: Nakamura
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hanafusa
authors.forename: Norio
authors.initials: N
authors.lastname: Komatsu
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D049109:Cell Proliferation / Q000187:drug effects; D003001:Cloning, Molecular; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D015972:Gene Expression Regulation, Neoplastic; D016313:Genes, abl; D006801:Humans; D020014:K562 Cells; D015363:Quinolones / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D015363:Quinolones; D051231:Farnesyltranstransferase; C402769:tipifarnib