Decreased nucleotide excision repair activity and alterations of topoisomerase IIalpha are associated with the in vivo resistance of a P388 leukemia subline to F11782, a novel catalytic inhibitor of topoisomerases I and II.
OBJECTIVE
The purpose of the study was to investigate the mechanisms associated with antitumor activity and resistance to F11782, a novel dual catalytic inhibitor of topoisomerases with DNA repair-inhibitory properties.


METHODS
For that purpose, an F11782-resistant P388 leukemia subline (P388/F11782) has been developed in vivo and characterized.


RESULTS
Weekly subtherapeutic doses of F11782 (10 mg/kg) induced complete resistance to F11782 after 8 weekly passages. This resistant P388/F11782 subline retained some in vivo sensitivity to several DNA-topoisomerase II and/or I complex-stabilizing poisons and showed marked collateral sensitivity to cisplatin, topotecan, colchicine, and Vinca alkaloids, while proving completely cross-resistant only to merbarone and doxorubicin. Therefore, resistance to F11782 did not appear to be associated with a classic multidrug resistance profile, as further reflected by unaltered drug uptake and no overexpression of resistance-related proteins or modification of the glutathione-mediated detoxification process. In vivo resistance to F11782 was, however, associated with a marked reduction in topoisomerase IIalpha protein (87%) and mRNA (50%) levels, as well as a diminution of the catalytic activity of topoisomerase IIalpha. In contrast, only minor reductions in topoisomerases IIbeta and I levels were recorded. However, of major interest, nucleotide excision repair activity was decreased 3-fold in these P388/F11782 cells and was more specifically associated with a decreased (67%) level of XPG (human xeroderma pigmentosum group G complementing protein), an endonuclease involved in this DNA repair system.


CONCLUSIONS
These findings suggest that both topoisomerase IIalpha and XPG are major targets of F11782 in vivo and further demonstrate the original mechanism of action of this novel compound.
Kruczynski
Anna
A
Division of Experimental Cancer Research, Pierre Fabre Research Center, Castres, Cedex, France. anna.kruczynski@pierre-fabre.com
Barret
Jean-Marc
JM
Van Hille
Benoît
B
Chansard
Nathalie
N
Astruc
Jackie
J
Menon
Yoann
Y
Duchier
Carole
C
Créancier
Laurent
L
Hill
Bridget T
BT
D000818:Animals; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D015152:Blotting, Northern; D002384:Catalysis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use; D004260:DNA Repair; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005047:Etoposide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D007938:Leukemia / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D020125:Mutation, Missense; D009281:Naphthalenes / Q000008:administration & dosage / Q000627:therapeutic use*; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000627:therapeutic use; D011714:Pyrans / Q000008:administration & dosage / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009281:Naphthalenes; D009943:Organophosphorus Compounds; D011714:Pyrans; D012333:RNA, Messenger; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C061400:etoposide phosphate; D005047:Etoposide; D004317:Doxorubicin; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D002945:Cisplatin; C405744:tafluposide