Sequence effect of irinotecan (CPT-11) and topoisomerase II inhibitors in vivo.
The DNA topoisomerases I and II are the target of several clinically important antineoplastic agents which produce DNA cleavage by stabilization of the covalent DNA-protein bond with resultant cell death after DNA synthesis is attempted. Depletion of the target topoisomerase and reciprocal changes in the other occur with drug treatment.


OBJECTIVE
To develop empiric treatment regimens of combinations and sequences of agents directed against topoisomerase I (irinotecan/CPT-11) and II (etoposide and doxorubicin), in vivo studies were performed in mice bearing the EMT-6 mammary tumor to assess efficacy, host tolerance and the resultant biochemical changes in topoisomerase mRNA and protein.


RESULTS
At 24 h after therapy, depletion of the target topoisomerase mRNA and protein with reciprocal increases in the alternate topoisomerase mRNA and, to a lesser extent, protein were noted. No therapeutic antagonism was found with any combination or sequence of agents, and therapeutic antagonism was noted with concurrent irinotecan/etoposide and sequential doxorubicin/irinotecan. Depletion of target topoisomerases by combined therapy beyond a threshold necessary for therapeutic efficacy produced no additional benefit.


CONCLUSIONS
Antineoplastic therapy with combinations of topoisomerase I and II agents is feasible and may produce therapeutic synergy. The appropriate sequence may depend on the particular agents used. The rationale for such therapy, that topoisomerases I and II may have reciprocal and compensatory interactions, is supported by the biochemical data.
Eder
J P
JP
Dana-Farber Cancer Institute and Joint Center for Radiation Therapy, Boston, MA 02115, USA.
Chan
V
V
Wong
J
J
Wong
Y W
YW
Ara
G
G
Northey
D
D
Rizvi
N
N
Teicher
B A
BA
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D016923:Cell Death / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism*; D004317:Doxorubicin / Q000008:administration & dosage; D004347:Drug Interactions; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D000077146:Irinotecan; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000378:metabolism; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D004273:DNA, Neoplasm; D012333:RNA, Messenger; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D000077146:Irinotecan; D004317:Doxorubicin; D002166:Camptothecin