Reduced DNA ligase activity in etoposide resistant human lymphatic leukaemia CEM cells.
Drug resistance is an obstacle preventing success of cancer chemotherapy. Resistance of vaccinia virus towards the topoisomerase II (topo II) targeting anti-cancer drug etoposide has been mapped to the viral DNA ligase gene. The present study was performed to elucidate if the DNA ligase activity, besides topo II levels, was altered in human lymphatic leukaemia cell strains with different levels of etoposide resistance. At measurements of DNA ligase activity with specific substrates, to distinguish between different DNA ligases, a reduced DNA ligase activity was observed in the resistant substrains. In contrast, the initial step of the ligation process, formation of DNA ligase--AMP complex, did not decrease in the resistant cell strains, suggesting an alteration in a later reaction leading to a deteriorated DNA ligation. The results suggest that decreased DNA ligase activity, besides topo II alterations, may contribute to etoposide resistance of the investigated CEM cells. The relevance of this finding will be further investigated.
Fredriksson
Eva
E
Institute of Environmental Medicine, Karolinska Institutet, P.O. Box 210, SE-171 77, Stockholm, Sweden.
Liliemark
Eva
E
Polischouk
Anya
A
Soderhall
Stefan
S
Albertioni
Freidoun
F
Ljungquist
Siv
S
D000249:Adenosine Monophosphate / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015153:Blotting, Western; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000032:analysis / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D007938:Leukemia / Q000201:enzymology*; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D000249:Adenosine Monophosphate; D005047:Etoposide; D004250:DNA Topoisomerases, Type II; D011088:DNA Ligases; D000072481:DNA Ligase ATP