Doxorubicin-induced DNA breaks, topoisomerase II activity and gene expression in human melanoma cells.
We have analyzed five human melanoma cell lines, displaying variable doxorubicin resistance (1- to 6-fold), for drug-induced DNA breaks, topoisomerase II activity and mRNA expression. Enhanced drug efflux was not the reason for doxorubicin resistance of these tumor cells although they overexpressed the transmembrane 170 kDa P-glycoprotein. Doxorubicin-induced DNA lesions (2-fold) and topoisomerase II activity (7-fold) were higher in HM-1 and G361 cells than in the less doxorubicin-sensitive NH and FCCM-9 cells. Topoisomerase II mRNA expression was also 2-fold higher in HM-1 and G361 cells. Doxorubicin-induced DNA breaks and topoisomerase II activity inversely correlated with the degree of doxorubicin sensitivity. Southern blot analysis showed variation in the hybridization pattern of topoisomerase II gene in doxorubicin-resistant cells when compared to sensitive cells. This study portrays the low doxorubicin sensitivity of NH and FCCM-9 cells as "atypical" and emphasizes the importance of DNA damage and topoisomerase II activity in cellular low doxorubicin resistance.
Department of Radiation Oncology, University of Miami, School of Medicine, FL 33136.
C
C
Ramachandran
T S
TS
Samy
X L
XL
Huang
Z K
ZK
Yuan
A
A
Krishan
D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology*; D004351:Drug Resistance; D015870:Gene Expression; D006801:Humans; D008545:Melanoma / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II