tafluposide and Leukemia

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

Topics: Animals; Antigens, Neoplasm; Antineoplastic Agents; Blotting, Northern; Catalysis; Cell Line, Tumor; Cisplatin; DNA Repair; DNA Topoisomerases, Type I; DNA Topoisomerases, Type II; DNA-Binding Proteins; Doxorubicin; Drug Resistance, Neoplasm; Etoposide; Leukemia; Mice; Mice, Inbred DBA; Mutation, Missense; Naphthalenes; Neoplasm Transplantation; Neoplasms, Experimental; Organophosphorus Compounds; Pyrans; RNA, Messenger; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors

Tafluposide (F 11782), a novel epipodophylloid with a unique mechanism of interaction with both topoisomerase I and II, has shown outstanding antitumor activity in vivo against a panel of experimental human tumor xenografts. The aim of this study was to evaluate its cytotoxicity against fresh tumor cells taken from patients. Cells derived from bone marrow, peripheral blood, malignant effusions or solid biopsies from 84 patients with either hematological or solid tumors were exposed continuously to 0.8-100 nuM tafluposide for 48 h, 96 h or 7 days. Cell survival was measured using an MTT assay or the ATP assay and LC(50) values (drug concentration required for 50% cell kill) were calculated. Tafluposide showed significant cytotoxicity against cells derived from either hematological or solid tumors, with a marked inter-patient variation. There was no significant difference between the effect of tafluposide in samples from untreated or previously treated patients (p>0.05 for all cancer types). Whilst tafluposide appeared to show weak (p<0.05) cross-resistance with the topoisomerase II inhibitor etoposide in acute myeloid leukemia (AML), there did not appear to be any correlation with the effect of the topoisomerase I inhibitor topotecan (p>0.05) in either hematological or solid malignancies. True synergism was identified when combining tafluposide with cisplatin in ovarian cancer [combination index (CI)=0.14, 0.79] and with etoposide in AML (CI=0.49, 0.63 and 0.78). Our results suggest that tafluposide is a strong candidate for inclusion in clinical trials, particularly in hematological malignancies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Lethal Dose 50; Leukemia; Naphthalenes; Ovarian Neoplasms; Pyrans; Topoisomerase Inhibitors; Tumor Cells, Cultured