The teratogenic effect of 5-trifluoromethyl-2?-deoxyuridine in chicken embryos

Kury, George; Crosby, Roberta J.

doi:10.1016/0041-008x(67)90028-2

Cited by 15 publications

(2 citation statements)

References 6 publications

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“…TFT, unlike ISIS 1082 and ACV, significantly affected incorporation of [3H]thymidine into HeLa cells (Table 1). The apparent biphasic effect of the compound, i.e., stimulation of precursor incorporation at low concentrations of TFT, which more than likely represents activation of the DNA repair synthetic machinery, and the severe inhibition of DNA synthesis at 100 jxM, are consistent with reports indicating the potential mutagenic and teratogenic effects of the compound (13,20). These data and preliminary in vivo data demonstrating that ISIS 1082 was effective in reducing the severity of HSV-induced stromal keratitis in mice (3) suggest that this compound may be a highly selective, minimally toxic therapeutic agent for the treatment of ocular herpetic keratitis.…”

Section: Discussionsupporting

confidence: 88%

“…Plates were washed with double-distilled H20, dried, and counted. (20 p,Ci/ml), and [3H]leucine (40 ,uCi/ml) was added to separate wells, and plates were incubated at 37°C for an additional 2 h. Following a 2-h pulse with 3H-precursors, plates were placed on ice, the media were removed, and cells were washed with 200 ,ul of 0.15 M NaCl. After being washed, cells were lysed with 25 RI of 0.2 M NaOH for 20 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

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In vitro toxicological evaluation of ISIS 1082, a phosphorothioate oligonucleotide inhibitor of herpes simplex virus

Crooke

Hoke

Shoemaker

1992

Antimicrob Agents Chemother

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ISIS 1082, a phosphorothioate oligonucleotide targeted to a translation initiation codon of herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) virion capsid protein UL13 inhibits in vitro viral replication. To better understand the pharmacological properties of ISIS 1082, we examined its effects in nonvirally infected HeLa cells by using a number of cytotoxicity assays. Our data indicate that ISIS 1082 had no effect on HeLa cell viability as measured by cellular proliferation and clonogenic assays at concentrations as high as 100 p1M. Additionally, DNA, RNA, and protein syntheses were only inhibited by 25% in cells treated with 100 FM ISIS 1082. The effects of ISIS 1082 on DNA synthesis were compared with those of acyclovir and trifluorothymidine, two clinically used antiherpetic agents. Acyclovir displayed effects similar to that of ISIS 1082. However, trifluorothymidine, which has been reported to be a potential mutagen and teratogen, significantly altered DNA replication at concentrations from 1 to 100 p,M. Isolated HeLa DNA polymerases were inhibited by the compound, with a 50%o inhibitory concentration of 2 pM. The in vitro antiviral (K.Draper and V. Brown-Driver, submitted for publication; K. G. Draper and V. Brown-Driver, Antiviral Res. Suppl. 1:106, 1991) and cytotoxicity studies suggest that ISIS 1082 is a selective, nontoxic, antiherpetic therapeutic agent.Herpes simplex virus (HSV) is the etiologic agent responsible for a variety of diseases, including ocular herpetic keratitis, an illness that can lead to severe corneal scarring and blindness (16,23). Patients with this condition may be treated with several drugs, including the nucleoside analogs acyclovir (ACV) and trifluorothymidine (TFT) (21, 31). Although each of the antiviral drugs has displayed clinical efficacy, the emergence of resistant strains of HSV and the occurrence of toxic and hypersensitivity reactions to the compounds underscore the need for more specific, potent, and less toxic antiviral therapy (25).The theoretical selectivity of antisense oligonucleotides for specific genomic and viral RNA targets makes their use as therapeutic agents extremely attractive (17,29,32). Our laboratory has designed and tested several sequence-specific oligonucleotides targeted to the translation initiation regions of HSV mRNAs (9, 10). ISIS 1082, a phosphorothioate oligonucleotide 21 nucleotides in length (5' GCCGAGGTC CATGTCGTACGC 3') is complementary to a translation initiation codon region within the UL13 open reading frame of HSV. The UL13 sequence is highly conserved within strains of HSV, and the target sites for ISIS 1082 are identical in HSV type 1 (HSV-1) and HSV-2, except for the 3'-terminal base of the target mRNAs. On the basis of sequence homology with other virus RNAs, the UL13 gene product is postulated to be a virion capsid protein with phosphotransferase activity (7,24). ISIS 1082 inhibited HSV-1 replication in cell culture in a dose-dependent manner, with 50% inhibitory concentrations (IC50s) ranging from 0.4...

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Section: Discussionsupporting

confidence: 88%

Section: Methodsmentioning

confidence: 99%