title: BCR-ABL-mediated inhibition of apoptosis with delay of G2/M transition after DNA damage: a mechanism of resistance to multiple anticancer agents.
abstract: A critical determinant of the efficacy of antineoplastic therapy is the response of malignant cells to DNA damage induced by anticancer agents. The p53 tumor-suppressor gene is a critical component of two distinct cellular responses to DNA damage, the induction of a reversible arrest at the G1/S cell cycle checkpoint, and the activation of apoptosis, a genetic program of autonomous cell death. Expression of the BCR-ABL chimeric gene produced by a balanced translocation in chronic myeloid leukemia, confers resistance to multiple genotoxic anticancer agents. BCR-ABL expression inhibits the apoptotic response to DNA damage without altering either the p53-dependent WAF1/CIP1-mediated G1 arrest or DNA repair. BCR-ABL-mediated inhibition of DNA damage-induced apoptosis is associated with a prolongation of cell cycle arrest at the G2/M restriction point; the delay of G2/M transition may allow time to repair and complete DNA replication and chromosomal segregation, thereby preventing a mitotic catastrophe. The inherent resistance of human cancers to genotoxic agents may result not only by the loss or inactivation of the wild-type p53 gene, but also by genetic alterations such as BCR-ABL that can delay G2/M transition after DNA damage.
authors.affiliation: Johns Hopkins Oncology Center, Baltimore, MD 21287, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bedi
authors.forename: J P
authors.initials: JP
authors.lastname: Barber
authors.forename: G C
authors.initials: GC
authors.lastname: Bedi
authors.forename: W S
authors.initials: WS
authors.lastname: el-Deiry
authors.forename: D
authors.initials: D
authors.lastname: Sidransky
authors.forename: M S
authors.initials: MS
authors.lastname: Vala
authors.forename: A J
authors.initials: AJ
authors.lastname: Akhtar
authors.forename: J
authors.initials: J
authors.lastname: Hilton
authors.forename: R J
authors.initials: RJ
authors.lastname: Jones
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001483:Base Sequence; D002453:Cell Cycle; D002908:Chronic Disease; D004249:DNA Damage; D004253:DNA Nucleotidylexotransferase / Q000378:metabolism; D004260:DNA Repair; D004351:Drug Resistance; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D066298:In Vitro Techniques; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology*; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D011839:Radiation, Ionizing; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016044:Fusion Proteins, bcr-abl; D004253:DNA Nucleotidylexotransferase