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.