Incorporation of 1-beta-D-arabinofuranosylcytosine into DNA from herpes simplex virus resistant to 9-beta-D-arabinofuranosyladenine.
We have demonstrated previously that 1-beta-D-arabinofuranosylcytosine (ara-C) incorporates specifically in cellular DNA and that the formation of (ara-C)DNA correlates significantly with inhibition of DNA synthesis and loss of clonogenic survival. Similar results have been obtained with 9-beta-D-arabinofuranosyl-adenine (ara-A). These findings have been extended by studying the incorporation of ara-C in DNA of a wild-type herpes simplex virus (HSV) and a mutant virus resistant to ara-C and ara-A. The results demonstrate that HSV resistance to ara-A is associated with formation of less (ara-C)DNA and less inhibition of DNA synthesis when compared to wild-type virus. This effect on formation of (ara-C)DNA is reversed upon exposure to higher (greater than 10(-6) M) ara-C concentrations, and this pattern of resistance corresponds to drug effect on virus plaque formation. The results also demonstrate a highly significant relationship between incorporation of ara-C in HSV DNA and inhibition of DNA synthesis for both viruses. Further, higher concentrations of ara-C that result in greater inhibition of DNA synthesis are associated with an increasing number of ara-C residues at the 3'-terminus of the DNA strand, thus suggesting that ara-C functions as a poor primer terminus for viral chain elongation. These results also suggest that HSV cross-resistance to ara-A and ara-C may be related to an altered viral DNA polymerase and that incorporation of ara-C in HSV DNA is at least one mechanism responsible for slowing viral synthesis and inducing lethal events.
D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D003561:Cytarabine / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects; D004279:DNA, Viral / Q000235:genetics* / Q000302:isolation & purification; D004352:Drug Resistance, Microbial; D007668:Kidney; D007700:Kinetics; D010761:Phosphorus Radioisotopes; D018139:Simplexvirus / Q000187:drug effects / Q000235:genetics*; D014316:Tritium; D014740:Vidarabine / Q000633:toxicity*
D004279:DNA, Viral; D010761:Phosphorus Radioisotopes; D003561:Cytarabine; D014316:Tritium; D014740:Vidarabine