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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1148-1158 |
| Number of pages | 11 |
| Journal | Blood |
| Volume | 86 |
| Issue number | 3 |
| State | Published - 1995 |
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ASJC Scopus subject areas
- Hematology
Cite this
BCR-ABL-mediated inhibition of apoptosis with delay of G2/M transition after DNA damage : A mechanism of resistance to multiple anticancer agents. / Bedi, Atul; Barber, J. P.; Bedi, G. C.; El-Deiry, W. S.; Sidransky, David; Vala, M. S.; Akhtar, A. J.; Hilton, J.; Jones, Richard J.
In: Blood, Vol. 86, No. 3, 1995, p. 1148-1158.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - BCR-ABL-mediated inhibition of apoptosis with delay of G2/M transition after DNA damage
T2 - A mechanism of resistance to multiple anticancer agents
AU - Bedi, Atul
AU - Barber, J. P.
AU - Bedi, G. C.
AU - El-Deiry, W. S.
AU - Sidransky, David
AU - Vala, M. S.
AU - Akhtar, A. J.
AU - Hilton, J.
AU - Jones, Richard J
PY - 1995
Y1 - 1995
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=0029131231&partnerID=8YFLogxK
M3 - Article
C2 - 7620167
AN - SCOPUS:0029131231
VL - 86
SP - 1148
EP - 1158
JO - Blood
JF - Blood
SN - 0006-4971
IS - 3
ER -