The anti-human immunodeficiency virus agent 3'-fluorothymidine induces DNA damage and apoptosis in human lymphoblastoid cells.
Patients infected with the human immunodeficiency virus experienced severe hematopoietic toxicity after treatment with the deoxynucleoside analog 3'-fluorothymidine (FLT). Using several methods for the analysis of genome integrity, including histochemical staining of the 3' ends of DNA and both conventional and pulsed-field agarose gel electrophoresis, we demonstrated that FLT caused extensive DNA fragmentation in CEM cells that was not observed when these cells were treated with other, less toxic thymidine analogs. In addition, a distinctive pattern of small DNA fragments that is characteristic of cells in the process of programmed cell death was observed in the genomic DNA of CEM cells treated with FLT. We conclude that FLT induces DNA fragmentation and apoptosis in a human cell line of hematopoietic origin, and we offer this observation as a possible explanation for the severe toxicity of FLT observed in vivo.
Sundseth
R
R
Division of Biochemistry, Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709, USA.
Joyner
S S
SS
Moore
J T
JT
Dornsife
R E
RE
Dev
I K
IK
D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity; D000998:Antiviral Agents / Q000378:metabolism / Q000633:toxicity*; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D002166:Camptothecin / Q000633:toxicity; D002460:Cell Line; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D015224:Dideoxynucleosides / Q000378:metabolism / Q000633:toxicity*; D004587:Electrophoresis, Agar Gel; D006801:Humans; D015215:Zidovudine / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D000998:Antiviral Agents; D015224:Dideoxynucleosides; C059694:raluridine; D015215:Zidovudine; D004247:DNA; C002854:alovudine; D002166:Camptothecin