Ak. Larsen et al., Unusual potency of BN 80915, a novel fluorinated E-ring modified camptothecin, toward human colon carcinoma cells, CANCER RES, 61(7), 2001, pp. 2961-2967
BN 80915 is the lead compound from a novel class of E-ring modified camptot
hecin analogues, the homoramptothecins, which show potent antitumor activit
ies in animal models. Here, we report that BN 80915 induces up to 2-fold mo
re cleavable complexes between plasmid DNA and purified human topoisomerase
I than SN-38 and camptothecin. BN 80915 also induces DNA-topoisomerase I c
omplexes in living MT-29 colon carcinoma cells, as shown by the in vivo lin
k assay. BN 80915 is an extremely potent inducer of DNA-protein complexes i
n these cells starting at a concentration of 5 nM in the media. BN 80915 is
clearly more potent than SN-38, because at least 20 times more SN-38 is ne
eded to induce comparable levels of cleavable complexes. Kinetic experiment
s show that BN 80915 induces cleavable complexes within minutes that remain
stable for at least 6 h in the presence of drug, Whereas the majority of t
he complexes are reversed within 15 min after drug removal, a substantial f
raction (30%) persists for at least 4 h, in contrast with SN-38-treated cel
ls, where all complexes have disappeared hy this time. BN 80915 shows stron
g antiproliferative effects toward HT-29 cells with an IC50 of 0.3 nM compa
red with 20 nM for SN-38 and 40 nM for topotecan, BN 80915 is also potent a
gainst other colon carcinoma cells as well as toward cells growing in three
dimensions as multicellular spheroids. HL-60 cells expressing functional P
-glycoprotein or multidrug resistance protein show no cross-resistance towa
rd BN 80915, Taken together, our results show that BN 80915 is unusually po
tent toward human colon carcinoma cells because of the formation of high le
vels of stable, covalent DNA-topoisomerase complexes,