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.
Ramachandran
C
C
Department of Radiation Oncology, University of Miami, School of Medicine, FL 33136.
Samy
T S
TS
Huang
X L
XL
Yuan
Z K
ZK
Krishan
A
A
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