Unusual potency of BN 80915, a novel fluorinated E-ring modified camptothecin, toward human colon carcinoma cells

Citation
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
Citations number
49
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER RESEARCH
ISSN journal
00085472 → ACNP
Volume
61
Issue
7
Year of publication
2001
Pages
2961 - 2967
Database
ISI
SICI code
0008-5472(20010401)61:7<2961:UPOB8A>2.0.ZU;2-8
Abstract
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,