Antitumor activities of a new indolocarbazole substance, NB-506, and establishment of NB-506-resistant cell lines, SBC-3/NB.
The novel anticancer glucosyl derivative of indolo-carbazole (NB-506), an inhibitor of DNA topoisomerase I, exhibited strong in vitro cytotoxicity against various human cancer cell lines. In order to elucidate its cytotoxic mechanisms, we established nine NB-506-resistant sublines with different resistance ratios from human small cell lung cancer cells (SBC-3/P) by stepwise and brief exposure (24 h) to NB-506. Among them, SBC-3/NB#9 was 454 times more resistant to NB-506 than the parent cell line. The SBC-3/NB#9 cells showed cross-resistance only to topoisomerase I inhibitors, such as 11,7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecia and 7-ethyl-10-hydroxy-camptothecin, and not to other anticancer drugs, such as vincristine, vinblastine, Adriamycin, etoposide, and teniposide. These results indicate that the difference on the effect of topoisomerase I was considered to be related to a resistance mechanism. The topoisomerase I activities of nuclear extracts eluted from SBC-3/NB#9 cells was only one-tenth of the parent cell activity. A Western blotting study indicated that this lower activity was due to a lower amount of DNA topoisomerase I. Furthermore, we found correlations between topoisomerase I activity and sensitivity to NB-506 in sublines with different degrees of resistance. Accumulation of 3H-labeled NB-506 by SBC-3/NB#9 cells was only one-fifth of that by the parent cells, whereas intracellular accumulation of 3H-labeled camptothecin by both cell lines did not differ. The reduction of accumulation was specific to NB-506, and this result may explain why the resistance ratio for NB-506 was higher than those for 11,7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin and 7-ethyl-10-hydroxy-camptothecin.
Kanzawa
F
F
Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan.
Nishio
K
K
Kubota
N
N
Saijo
N
N
D000970:Antineoplastic Agents; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology*; D018288:Carcinoma, Small Cell; D002467:Cell Nucleus / Q000201:enzymology; D004351:Drug Resistance; D005960:Glucosides / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D000077146:Irinotecan; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002227:Carbazoles; D005960:Glucosides; C092476:NB 506; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D002166:Camptothecin