Anti-tumour activities of a new benzo[c]phenanthridine agent, 2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]phena nthridini um hydrogensulphate dihydrate (NK109), against several drug-resistant human tumour cell lines.
Drug resistance is one of the problems severely limiting chemotherapy in cancer patients. Thus, it is very important to develop new drugs that are effective against drug-resistant tumour cells. The novel anti-tumour agent NK109 has been developed from benzo[c]phenanthridine derivatives by Nippon Kayaku (Tokyo, Japan). We have confirmed that NK109 shows anti-tumour effects against a number of human tumour cell lines by inhibiting DNA topoisomerase II activity through the stabilization of the cleavable complex. Further, its efficacy against several drug-resistant tumour cell lines was also shown. NK109 showed potent anti-tumour activity against doxorubicin-resistant human tumour cell lines that have a typical multidrug resistance phenotype caused by P-glycoprotein. NK109 was not pumped extracellularly by P-glycoprotein and, consequently, NK109 accumulated in resistant cells. Cisplatin-resistant human tumour cell lines, which demonstrated decreased cisplatin accumulation, were sensitive to NK109. NK109 non-cross-resistance was confirmed using xenografts of tumour cells that were resistant to cisplatin in SCID mice. Furthermore, etoposide-resistant cells, with decreased topoisomerase II activity, were markedly sensitive to NK109 when compared with their parent cells, suggesting the possibility that the cytotoxic mechanism of NK109 differs from that of etoposide. In conclusion, NK109 is a very promising new anti-tumour drug for clinical use, because the efficacy of NK109 is not susceptible to several known molecular alterations that are associated with drug resistance. A clinical study of this compound is now in progress in Japan.
Kanzawa
F
F
Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan. fkanzawa@gan2.ncc.go.jp
Nishio
K
K
Ishida
T
T
Fukuda
M
M
Kurokawa
H
H
Fukumoto
H
H
Nomoto
Y
Y
Fukuoka
K
K
Bojanowski
K
K
Saijo
N
N
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity*; D053119:Benzophenanthridines; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002945:Cisplatin / Q000493:pharmacokinetics / Q000633:toxicity; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005047:Etoposide / Q000633:toxicity; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D010617:Phenanthridines / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D053119:Benzophenanthridines; D008562:Membrane Glycoproteins; C108284:NK 109; D010617:Phenanthridines; D005047:Etoposide; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D002945:Cisplatin