DNA chain termination by 2',3'-dideoxythymidine in replicating mammalian cells

Byars, Noelene E.; Kidson, Chev

doi:10.1021/bi00685a019

Cited by 31 publications

(12 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In essence, sMtCK served as a critical control for localizing the AZT toxic effect to muscle mitochondrial genome and not elements of the mitochondrial matrix that are derived from expression of nuclear genes. This was consistent with postulated mechanisms of AZT's inhibition of replication of mtDNA (37,38,39) and not nuclear DNA. Based on Northern analysis, cytochrome b does not appear to be the sole target of AZT damage to the striated muscle mitochondrial genome, but decreases in both mtRNA and polypeptide synthesis following AZT treatment were striking.…”

Section: Discussionsupporting

confidence: 86%

See 1 more Smart Citation

Zidovudine induces molecular, biochemical, and ultrastructural changes in rat skeletal muscle mitochondria.

Lewis¹,

Gonzalez²,

Chomyn³

et al. 1992

J. Clin. Invest.

197

114

View full text Add to dashboard Cite

Zidovudine (AZT) inhibits HIV-1 replication in AIDS. A limiting side effect is AZT-induced toxic myopathy. Molecular changes in a rat model of AZT-induced toxic myopathy in vivo helped define pathogenetic molecular, biochemical, and ultrastructural toxic events in skeletal muscle and supported clinical and in vitro findings. After 35 d of AZT treatment, selective ehanges in rat striated muscle were localized ultrastructurally to mitochondria, and included swelling, cristae disruption, and myelin figures. Decreased muscle mitochondrial (mt) DNA, mtRNA, and decreased mitochondrial polypeptide synthesis in vitro were found in parallel. Mitochondrial molecular changes occurred in absence of altered abundance of cytosolic glyceraldehyde-3-phosphate dehydrogenase, or sarcomeric mitochondrial creatine kinase mRNAs. Quadriceps mitochondrial DNA polymerase gamma activity was similar in both AZT-treated and control rats. In vivo findings with rats support the hypotheis that AZT-induced inhibition of mtDNA replication has an tT. of depressing the abundance of striated muscle mtDNA,

show abstract

Section: Discussionsupporting

confidence: 86%

“…This supported in vitro pharmacologic and toxicologic data that suggested AZT interferes with mtDNA replication by mechanisms that involve mtDNA chain termination in vivo (37)(38)(39).…”

Section: Discussionsupporting

confidence: 72%

Zidovudine induces molecular, biochemical, and ultrastructural changes in rat skeletal muscle mitochondria.

Lewis¹,

Gonzalez²,

Chomyn³

et al. 1992

J. Clin. Invest.

197

114

View full text Add to dashboard Cite

show abstract

“…Thus, variation in effectiveness ofthe 2',3'-dideoxynucleosides from cell line to cell line may reflect variations in endogenous levels of the relevant kinases and the corresponding phosphorylases. The active phosphorylated analogues are thought to act as chain terminators once they are incorporated into the nascent chain during DNA synthesis (36)(37)(38). Indeed, Mitsuya et al (18) have shown that phosphorylated dideoxynucleotides terminate DNA chains synthesized de novo by HTLV-III/LAV reverse transcriptase.…”

Section: Methodsmentioning

confidence: 99%

Broad spectrum antiretroviral activity of 2',3'-dideoxynucleosides.

Dahlberg¹,

Mitsuya²,

Blam³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Certain dideoxynucleosides have been shown to markedly inhibit the infectivity of human T-lymphotropic virus type m/lymphadenopathy-associated virus, the causative agent of acquired immunodeficiency syndrome (AIDS). Our present studies demonstrate that these drugs are broad spectrum antiretroviral agents capable of inhibiting the infectivity of evolutionarily divergent mammalian type C and animal lentiviruses. Under some conditions, virus infectivity could be inhibited by more than six orders of magnitude. However, the potency of these agents was shown to be greatly influenced by cell-specified determinants. Drug exposure during the initial 24 hr was almost as effective as prolonged treatment on the inhibition of a single cycle of virus infection and expression. Moreover, virus infection was shown directly to be inhibited at the level of proviral DNA synthesis. Thus the time period during which reverse transcription and provirus integration occur is the critical period required for drug action.Our findings have implications concerning strategies to be considered in attempts to utilize 2',3'-dideoxynucleosides in control and treatment of retrovirus-induced diseases ofanimals and humans.In the past few years, efforts aimed at prevention and control of retroviral-induced diseases have gained increasing importance with accumulating evidence that such viruses are responsible for human as well as animal diseases. A potentially useful strategy has arisen from the application of a group of nucleoside analogues first synthesized over 20 years ago (1-5). These dideoxynucleosides were shown to inhibit the retroviral reverse transcriptase (6-8) as well as cellular DNA polymerases f3 and y, while polymerase a was relatively resistant (8-12). Initial studies aimed at demonstrating selective inhibition of viral replication by these drugs showed relatively modest effects (7,8). Recently, however, 3'-azido-3'-deoxythymidine (N3dThd; sometimes referred to as AZT) (13) and virtually all of the 2',3'-dideoxynucleosides (14) analyzed were found to powerfully and selectively inhibit replication of human T-lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV), § the retrovirus causative of acquired immunodeficiency syndrome (AIDS).The AIDS virus has been shown to be closely related to animal lentiviruses (15-17), whereas early investigations of these antiviral drugs focused upon distantly related type C viruses. Thus, it is not known whether the reported differences in their antiviral effects relate to host cell or viral specificities. Recently Mitsuya and his colleagues have shown that these nucleoside analogues act as chain terminators of the reverse transcription products of the incoming HTLV-III/LAV (18), although this need not be the only mechanism for antiretroviral activity. Our present studies demonstrate a broad spectrum of antiretroviral activity by these agents, but show considerable cell variation in the potency of different agents. Under optimal conditions, the selective inhibition of even a ...

show abstract

“…Despite the demonstrated inhibition of cellular and viral DNA polymerases by ddTTP in vitro, the nucleoside, 2',3'-dideoxythymidine (ddThd), has, in the hands of most investigators, very little effect on cell growth or virus replication in vivo, Cohen (1969, 1970) reported that 2',3'-dideoxyadenosine ( d a d o ) is lethal to E. coli, but under conditions where host bacteria are killed, d a d o does not interfere with the replication of T6 bacteriophage. Byars and Kidson (1975), Krokan et al, (1979) and Furmanski et al (1980) all report that ddThd has, at most, a mild inhibitory effect on the growth of mammalian cell lines and Smoler et al (1971) and Furmanski et al (1980) report that ddThd does not affect the replication of retroviruses in chicken cells or rat cells. However, Furmanski et al (1980) also found that ddThd does inhibit replication of several retroviruses in both mouse and human cells.…”

Section: Herpes Simplex Virus Type I (Hsv-i) Dna Polymerase Ismentioning

confidence: 99%

Effects of 2′,3′‐dideoxynucleosides on mammalian cells and viruses

Waqar

Evans

Manly

et al. 1984

Journal Cellular Physiology

127

View full text Add to dashboard Cite

Previous studies on the biological effects of the 2',3'-dideoxynucleosides (ddNs) have shown that while ddAdo is lethal to E. coli, ddThd has minimal effects on the growth of mammalian cell lines and that it inhibits retrovirus infection of some cell lines but not others. Previous studies have also shown that the 5'-triphosphate of ddThd, ddTTP, selectively inhibits cellular DNA polymerases beta and gamma and retroviral reverse transcriptases. Cellular DNA polymerase alpha is relatively resistant to ddTTP. We have extended these findings to show that the 5'-triphosphates of the other 3 ddNs (ddATP, ddCTP, and ddGTP) affect cellular DNA polymerases alpha, beta, and gamma in the same fashion as does ddTTP. We also show that all four ddNs in concentrations up to 100 microM have negligible effects on the growth of NIH Swiss 3T3 cells. These negligible effects may be due to inefficient intracellular phosphorylation of each nucleoside to the triphosphate. We have determined that, in several different cell lines, ddThd is phosphorylated only at a very slow rate to ddTTP, and in the one cell line tested (monkey CV-1 cells), ddAdo and ddGuo are also poorly phosphorylated. Both ddAdo and ddGuo, and probably ddThd, are converted by CV-1 cells to additional unknown compounds which may have biological activity. The four ddNs display effects of different magnitudes on certain virus infections. Although 30 microM ddThd inhibits herpes simplex I infection of CV-1 cells by 50%, 30 microM ddAdo has no effect. Infection of NIH Swiss 3T3 cells by 334C murine leukemia virus is inhibited 70-80% by ddAdo, ddCyd, and ddThd at 50 microM, but inhibition by 50 microM ddGuo is 100%.

show abstract

DNA chain termination by 2',3'-dideoxythymidine in replicating mammalian cells

Cited by 31 publications

References 11 publications

Zidovudine induces molecular, biochemical, and ultrastructural changes in rat skeletal muscle mitochondria.

Zidovudine induces molecular, biochemical, and ultrastructural changes in rat skeletal muscle mitochondria.

Broad spectrum antiretroviral activity of 2',3'-dideoxynucleosides.

Effects of 2′,3′‐dideoxynucleosides on mammalian cells and viruses

Contact Info

Product

Resources

About