The anti-human immunodeficiency virus agent 3'-fluorothymidine induces DNA damage and apoptosis in human lymphoblastoid cells

Abstract

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.

Apoptosis and apoptosis-associated perturbations of peripheral blood lymphocytes during HIV infection: comparison between AIDS patients and asymptomatic long-term non-progressors

“…The relative contribution of zidovudine to the increased lymphocyte apoptosis is unclear. Zidovudine and other nucleoside analogues have been shown to induce apoptosis in several in vitro systems [43–46]. In clinical studies of anti‐retroviral therapy however, the suppression of viral replication is not clearly associated with a decline in lymphocyte apoptosis [47–49].…”

Premature and accelerated aging: HIV or HAART?

“…DNA damage and unreliable replication can be induced by the backbone of antiretroviral therapy, namely NRTIs (Sundseth et al, 1996; Payne et al, 2011). NRTIs have been shown to inhibit the mitochondrial specific DNA polymerase-γ causing a decrease in mtDNA amount and quality.…”

“…Additionally, antiretroviral therapy likely hastens the expansion of pre-existing mutations in mtDNA as depleted mtDNA pools display accelerated digression from their original genetic content (Khrapko, 2011; Payne et al, 2011). The NRTI 3′-deoxy-3′-fluorothymidine ( alovudine or FLT), known for its high toxicity, can cause DNA fragmentation and induce apoptosis (Sundseth et al, 1996). Interestingly, the NRTIs 3′-azido-3′-deoxythymidine ( zidovudine or AZT) and 2′,3′-didehydro-2′,3′-deoxythymidine ( stavudine or d4T) also disrupt telomerase maintenance and have telomere shortening effects, properties often related to cell senescence and aging (Strahl and Blackburn, 1994; Blasco, 2007).…”

“…Hematopoietic progenitor and lymphoblastoid cell toxicity of NRTIs may explain immune cell depletion independent of inflammation (Faraj et al, 1994; Sundseth et al, 1996; Sharma, 2010). Moreover, a decline in mitochondrial genetic integrity in hematopoietic progenitor cells could also explain continued immune dysfunction upon cessation of therapy.…”

Nucleoside and nucleotide inhibitors of HIV-1 replication

“…Side effects of alovudine are related to bone marrow damage, which includes liver toxicity and anaemia. Sundseth et al [239] reported that FLT caused extensive DNA fragmentation and induced apoptosis in CEM cells, providing a possible mechanism for its toxicity. In early clinical trials, the most common side effects reported were anaemia and neutropaenia.…”