Lack of cross-resistance to fostriecin in a human small-cell lung carcinoma cell line showing topoisomerase II-related drug resistance.
Cells exhibiting decreased topoisomerase II (Topo II) activity are resistant to several drugs that require Topo II as an intermediate. These drugs are cytotoxic due to the formation of a cleavable complex between the drug, Topo II and DNA. Fostriecin belongs to a new class of drugs that inhibit Topo II without inducing the formation of this cleavable complex. We tested fostriecin in three human small-cell lung carcinoma cell lines. GLC4 is the parent line. GLC4/ADR is the P-glycoprotein-negative multidrug-resistant subline, which is resistant to several Topo II inhibitors due to its decreased Topo II activity. GLC4/cDDP is the cisplatin-resistant subline, which displays increased Topo II activity. Topo II activity proved to be 100% in GLC4, 35% in GLC4/ADR and 130% in GLC4/cDDP. The fostriecin concentration causing inhibition of the growth of 50% of the cells (IC50) in the microculture tetrazolium assay following continuous incubation was 11.2, 4.1 and 14.9 microM, respectively. After 1-h incubations, the IC50 was 117.8, 101.3 and 219.8 microM, respectively. Our results indicate a relationship between Topo II activity and fostriecin sensitivity in these closely related cell lines. At least in vitro, fostriecin displayed the capacity to kill cells showing resistance to drugs due to decreased Topo II activity. There was no relationship between this capacity and an increase in the activity of the reduced-folate carrier system, the proposed mechanism for cellular entry of fostriecin, since we found no correlation between the cytotoxicity of fostriecin and that of methotrexate.
de Jong
S
S
Department of Internal Medicine, University Hospital Groningen, The Netherlands.
Zijlstra
J G
JG
Mulder
N H
NH
de Vries
E G
EG
D000475:Alkenes / Q000037:antagonists & inhibitors / Q000633:toxicity; D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors* / Q000633:toxicity; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000201:enzymology; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology; D004250:DNA Topoisomerases, Type II / Q000187:drug effects* / Q000302:isolation & purification; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005047:Etoposide / Q000633:toxicity; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D008727:Methotrexate / Q000633:toxicity; D011090:Polyenes; D011753:Pyrones; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
D000475:Alkenes; D000903:Antibiotics, Antineoplastic; D011090:Polyenes; D011753:Pyrones; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D004250:DNA Topoisomerases, Type II; D008727:Methotrexate; C040313:fostriecin