![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 57, Issue 2, 296-307, February 2000
and Altered G2/M Checkpoint
and Apoptotic Responses
Department of Molecular Genetics, University of Illinois at
Chicago, Chicago, Illinois (S.E.M., R.S.C., W.T.B.); and Department of
Pathology and Laboratory Medicine, St. Jude Children's Research
Hospital, Memphis, Tennessee (S.C.R.).
ICRF-187 is a bisdioxopiperazine anticancer drug that inhibits the
catalytic activity of DNA topoisomerase (topo) II without stabilizing
DNA-topoII cleavable complexes. To better understand the mechanisms of
action of and resistance to topoII catalytic inhibitors, human leukemic
CEM cells were selected for resistance to ICRF-187. The clones
CEM/ICRF-8 and CEM/ICRF-18 are approximately 40- and 69-fold resistant
to ICRF-187, and 12- and 67-fold cross-resistant to ICRF-193,
respectively, but are sensitive to other topoII catalytic inhibitors
(merbarone and aclarubicin), as well as collaterally sensitive to the
DNA-topoII complex-stabilizing drug etoposide (VP-16). Both the number
of VP-16- induced DNA-topoII complexes formed and the amount of in
vitro topoII catalytic activity are enhanced in the drug-resistant
cells. The ICRF-187-resistant clones contain ~5-fold increase in
topoII
protein levels and ~2.2-fold increase in topoII mRNA
levels. Furthermore, CEM/ICRF-8 expresses ~3.5-fold increase in
topoII promoter activity, suggesting that up-regulation of topoII
in this clone occurs at the transcriptional level. Treatment of the
drug-resistant or -sensitive cells with equitoxic doses of merbarone or
teniposide results in a G2/M arrest. In marked contrast,
when treated with equitoxic ICRF-187 doses, the drug-resistant clones
exhibit either a transient arrest or completely lack the
G2/M checkpoint compared with the drug-sensitive cells.
This aberrant cell cycle profile is associated with a 48-h delay in
drug-induced apoptotic cell death, as revealed by fluorescent-end labeling of DNA and poly (ADP-ribose) polymerase cleavage. In summary,
resistance to ICRF-187 in CEM cells is associated with increased levels
of catalytically active topoII and altered G2/M checkpoint and apoptotic responses.
This article has been cited by other articles:
|
|
 |
|
  T. Yan, S. Deng, A. Metzger, U. Godtel-Armbrust, A. C.G. Porter, and L. Wojnowski Topoisomerase II{alpha}-dependent and -independent apoptotic effects of dexrazoxane and doxorubicin Mol. Cancer Ther., May 1, 2009; 8(5): 1075 - 1085. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kruczynski, J.-M. Barret, B. van Hille, N. Chansard, J. Astruc, Y. Menon, C. Duchier, L. Creancier, and B. T. Hill Decreased Nucleotide Excision Repair Activity and Alterations of Topoisomerase II{alpha} Are Associated with the in Vivo Resistance of a P388 Leukemia Subline to F11782, a Novel Catalytic Inhibitor of Topoisomerases I and II Clin. Cancer Res., May 1, 2004; 10(9): 3156 - 3168. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Kang and I. K. Chung Down-Regulation of DNA Topoisomerase IIalpha in Human Colorectal Carcinoma Cells Resistant to a Protoberberine Alkaloid, Berberrubine Mol. Pharmacol., April 1, 2002; 61(4): 879 - 884. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. B. Hasinoff, M. E. Abram, N. Barnabé, T. Khélifa, W. P. Allan, and J. C. Yalowich The Catalytic DNA Topoisomerase II Inhibitor Dexrazoxane (ICRF-187) Induces Differentiation and Apoptosis in Human Leukemia K562 Cells Mol. Pharmacol., March 1, 2001; 59(3): 453 - 461. [Abstract] [Full Text]
|
|
|
|
|
|
S. E. Morgan and W. T. Beck Role of an Inverted CCAAT Element in Human Topoisomerase II{alpha} Gene Expression in ICRF-187-Sensitive and -Resistant CEM Leukemic Cells Mol. Pharmacol., February 1, 2001; 59(2): 203 - 211. [Abstract] [Full Text]
|
|
|
|
 |
|
 B. B. Hasinoff, M. E. Abram, G.-L. Chee, E. Huebner, E. H. Byard, N. Barnabé, V. J. Ferrans, Z.-X. Yu, and J. C. Yalowich The Catalytic DNA Topoisomerase II Inhibitor Dexrazoxane (ICRF-187) Induces Endopolyploidy in Chinese Hamster Ovary Cells J. Pharmacol. Exp. Ther., November 1, 2000; 295(2): 474 - 483. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
