Synergistic effects of F 11782, a novel dual inhibitor of topoisomerases I and II, in combination with other anticancer agents.
OBJECTIVE
F 11782, or 2',3'-bis-pentafluorophenoxyacetyl-4',6'-ethylidine-beta- D-glucoside of 4'-phosphate-4'-dimethylepipodophyllotoxin 2 N-methyl glucamine salt, a novel dual catalytic inhibitor of topoisomerases I and II, characterized by marked antitumour activity in vivo in a series of experimental murine and human tumours, has been selected for further development. This preclinical study was undertaken to investigate its potential for inclusion in combination chemotherapy regimens. The in vitro cytotoxicity of F 11782 incubated simultaneously with the following drugs was investigated: aclarubicin, cisplatin, doxorubicin, etoposide, 5-fluorouracil, mitomycin C, paclitaxel, topotecan or vinorelbine.


METHODS
The combinations were first evaluated in vitro against the GCT27 human testicular teratoma cell line and then against the A549 human non-small cell lung cancer cell line using median effect analysis.


RESULTS
F 11782 in combination with cisplatin, mitomycin C, etoposide or doxorubicin showed synergistic cytotoxicity against both cell lines. Moreover, F 11782 combined with cisplatin or mitomycin C showed antitumour activity in vivo against P388 murine leukaemia grafted intravenously. Such synergy might have resulted from the identified nucleotide excision repair inhibitory activity of F 11782.


CONCLUSIONS
F 11782 appears to be a promising candidate for combination chemotherapy, especially with DNA-damaging agents.
Barret
Jean-Marc
JM
Division de Cancérologie, Centre de Recherche Pierre Fabre, 17 avenue Jean Moulin, 81100 Castres, France.
Kruczynski
Anna
A
Etiévant
Chantal
C
Hill
Bridget T
BT
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009281:Naphthalenes / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D011714:Pyrans / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000201:enzymology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D011714:Pyrans; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C405744:tafluposide