title: Increased sensitivity to cytosine arabinoside in human leukemia by c-raf-1 antisense oligonucleotides.
abstract: c-raf-1, a cytoplasmic serine/threonine protein kinase, plays an important role in mitogen- and damage-responsive cellular signal transduction pathways. Expression of c-raf-1 modifies cell growth, proliferation and survival. Although expression of c-raf-1 has been studied in several tumors, the role of c-raf-1 in leukemia is so far unclear. We examined the expression of c-raf-1 in the human leukemia cell lines U937 and K562, and in a cytosine arabinoside (Ara-C)-resistant cell line (K562AC) derived from K562. Expression of c-raf-1 was increased in U937 and in Ara-C-resistant K562AC cells compared with the parental cells. We then investigated whether inhibition of c-raf-1 expression by antisense oligonucleotides increases the sensitivity to Ara-C in U937 and K562AC cells. Antisense oligonucleotides for c-raf-1 inhibited expression of c-raf-1 mRNA, but did not affect cell growth and increased sensitivity to Ara-C but not to other drugs such as adriamycin, VP-16 or vincristine. These results suggest that c-raf-1 is one of the factors involved in Ara-C resistance in leukemia and lend weight to the case for development of anti-cancer therapeutics involving oncogene-targeted antisense oligonucleotides.
authors.affiliation: Division of Molecular Diagnostics, Department of Clinical Medicine, Tohoku University, School of Medicine, Seiryoumachi 1-1, Aoba-ku, Sendai 980-8574, Japan. tfunato@mail.cc.tohoku.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Funato
authors.forename: K
authors.initials: K
authors.lastname: Kozawa
authors.forename: S
authors.initials: S
authors.lastname: Fujimaki
authors.forename: M
authors.initials: M
authors.lastname: Kaku
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D015152:Blotting, Northern; D002455:Cell Division / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020014:K562 Cells / Q000166:cytology / Q000187:drug effects*; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020298:U937 Cells / Q000166:cytology / Q000187:drug effects
chemical_list: D000964:Antimetabolites, Antineoplastic; D016376:Oligonucleotides, Antisense; D003561:Cytarabine; D019908:Proto-Oncogene Proteins c-raf