DNA topoisomerase II alpha expression is associated with alkylating agent resistance.
Increased expression of DNA topoisomerase II alpha has been associated with resistance to certain DNA-damaging alkylating agents, but no causal relationship or mechanism has been established. To investigate this observation, we developed a model of topoisomerase II overexpression by transfecting a full-length Chinese hamster ovary topoisomerase II alpha into EMT6 mouse mammary carcinoma. Topoisomerase II alpha-transfected cell lines demonstrated continued topoisomerase II alpha mRNA and protein expression, which were undetectable in vector-only lines, in stationary phase (G0-G1). The topoisomerase II transfectants were approximately 5-10-fold resistant to the alkylating agents cisplatin and mechlorethamine. Upon release from G0-G1, the topoisomerase II transfectants demonstrated more rapid thymidine incorporation and shorter cell-doubling times than control cells. Purified topoisomerase II and nuclear extracts with topoisomerase II-decatenating activity bound to cisplatin-treated DNA with significantly greater affinity than to untreated DNA in a cisplatin concentration-dependent manner. These observations suggest that expression of topoisomerase II alpha may have a role in cellular resistance to antineoplastic alkylating agents. The mechanism for this may involve increased binding of topoisomerase II alpha to alkylating agent-damaged DNA.
Eder
J P
JP
Thorndike Laboratories, Beth Israel Hospital, Boston, Massachusetts 02215, USA.
Chan
V T
VT
Ng
S W
SW
Rizvi
N A
NA
Zacharoulis
S
S
Teicher
B A
BA
Schnipper
L E
LE
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001483:Base Sequence; D016466:CHO Cells / Q000201:enzymology; D002945:Cisplatin / Q000737:chemistry; D006224:Cricetinae; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D017931:DNA Primers / Q000737:chemistry; D004261:DNA Replication; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D017931:DNA Primers; D012333:RNA, Messenger; D004247:DNA; D004250:DNA Topoisomerases, Type II; D002945:Cisplatin