title: Ex vivo effects of the dual topoisomerase inhibitor tafluposide (F 11782) on cells isolated from fresh tumor samples taken from patients with cancer.
abstract: 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.
authors.affiliation: Haematology Research, Pembury Hospital, Pembury, UK. jean.sargent@btinternet.com
authors.forename: Jean M
authors.initials: JM
authors.lastname: Sargent
authors.forename: Alena W
authors.initials: AW
authors.lastname: Elgie
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Williamson
authors.forename: Bridget T
authors.initials: BT
authors.lastname: Hill
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007928:Lethal Dose 50; D007938:Leukemia / Q000188:drug therapy*; D009281:Naphthalenes / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011714:Pyrans / Q000627:therapeutic use*; D059003:Topoisomerase Inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D009281:Naphthalenes; D011714:Pyrans; D059003:Topoisomerase Inhibitors; C405744:tafluposide