Immunosuppressive, antiviral and antitumor activities of cytarabine derivatives

Gray, Gary D.; Nichol, F. R.; Mickelson, Mary M.; Camiener, Gerald W.; Gish, Duane T.; Kelly, Robert C.; Wechter, William J.; Moxley, T. E.; Neil, Gary L.

doi:10.1016/0006-2952(72)90319-x

Cited by 39 publications

(20 citation statements)

References 26 publications

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“…Therapeutic synergism achieved by the use of a combination of drugs has been of considerable value in the treatment of bacterial and neoplastic disease (9)(10)(11)22). The rationale for combination therapy is that host toxicity is reduced because lower levels of drugs can be used.…”

Section: Resultsmentioning

confidence: 99%

“…5-Iodo-2'-deoxyuridine (IUdR) (21), 9-f3-n-arabinofuranosyladenine (Ara-A) (6,16), and 1-f3-n-arabinofuranosylcytosine (Ara-C) (25) have been found to be effective to varying degrees in the treatment of infections due to herpesviruses. However, their high toxicity (9,13,25), especially to rapidly proliferating cells (18,19), limits the usefulness of these nucleoside analogues in the treatment of viral infections. Recently, another nucleoside derivative, 5-methoxymethyl-2'-deoxyuridine (MMUdR), was synthesized (3), and in preliminary experiments it showed antiviral activity against infectious bovine rhinotracheitis virus (14).…”

mentioning

confidence: 99%

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Comparison of the Antiviral Effects of 5-Methoxymethyl-deoxyuridine with 5-Iododeoxyuridine, Cytosine Arabinoside, and Adenine Arabinoside

Meldrum²,

Vs³

et al. 1975

Antimicrob Agents Chemother

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The antiviral activity of 5-methoxymethyl-2′-deoxyuridine (MMUdR) was compared with that of 5-iodo-2′-deoxyuridine (IUdR), cytosine arabinoside (Ara-C), and adenine arabinoside (Ara-A). At concentrations of 2 to 4 μg/ml, MMUdR was inhibitory to herpes simplex virus type 1, but concentrations as high as 128 μg/ml were not inhibitory to three other herpesviruses tested (equine rhinopneumonitis virus, murine cytomegalovirus, and feline rhinopneumonitis virus) or to vaccinia virus. The other nucleosides, in contrast, were inhibitory at similar concentrations (1 to 8 μg/ml) against all viruses tested. The inhibition of HSV-1 by MMUdR appeared to be the result of interference with virus replication rather than the result of drug toxicity to host cells. The drug was not toxic to host cells at 100 times the antiviral concentrations, and pretreatment of host cells with high concentrations of MMUdR had no effect on subsequent virus replication. Combination of MMUdR with either IUdR, Ara-A, or Ara-C gave an enhanced antiviral effect, suggesting that the mechanism of action of MMUdR is different from that of the other three drugs. Antiviral indexes were calculated for each compound and were found to be >250, 80, 40, and 8 for MMUdR, IUdR, Ara-A, and Ara-C, respectively. These were defined as the minimum dose at which toxicity was observed microscopically divided by the dose which reduced plaque numbers by 50%.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Comparison of the Antiviral Effects of 5-Methoxymethyl-deoxyuridine with 5-Iododeoxyuridine, Cytosine Arabinoside, and Adenine Arabinoside

Meldrum²,

Vs³

et al. 1975

Antimicrob Agents Chemother

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“…For these and other patients studied by our serious risk of uncontrolled hemorrhage. Immune suppression of the humoral immune system predisposes patients to risk from secondary infections (1,3,10). Gastrointestinal and central nervous system toxicity also limit the usefulness of some of the potential antiviral compounds.…”

Section: Resultsmentioning

confidence: 99%

Effects of Adenine Arabinoside on Cellular Immune Mechanisms in Humans

Steele

Chapa²,

Vincent³

et al. 1975

Antimicrob Agents Chemother

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In vitro lymphocyte blastogenic responses to the commonly employed mitogens, phytohemagglutinin, pokeweed, and concanavalin A, were evaluated when adenine arabinoside (ara-A) in a concentration of 3 μg/ml was added to the culture materials. Similarly, blastogenic and cytotoxic responses to cell cultures persistently infected with herpes simplex virus 1, herpes simplex virus 2, and varicella-zoster virus were determined in the presence of ara-A. No depression of these cellular immune responses by ara-A was demonstrated. This was in contrast to the effect of cytosine arabinoside, which at a concentration of 3 μg/ml severely inhibited these immune responses. Further studies examined lymphocyte blastogenic responses to the mitogens and blastogenic and cytotoxic responses specific for the herpes group virus infecting patients who were subsequently treated with ara-A; determinations were made before, during, and after treatment. In vitro responses during and after treatment with ara-A were unchanged or often enhanced as compared to pretreatment values. Therefore, the antiviral chemotherapeutic agent, ara-A, does not appear to depress the host's cellular immune responses, which are vital to successful elimination of invading herpes group viruses.

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“…Subsequently a variety of other 5'-esters of araC were shown to be equally effective as antitumour agents in mice, in protecting mice from the lethal effects of intracranial herpes simplex infection, in inhibition of DNA synthesis in phytohemagglutinin-stimulated human lymphocytes, etc. [80] . The corresponding 2'-O-and 3'-O-esters proved less effective [81,82] .…”

Section: Hazards Associated With Nucleoside Antiviral Agentsmentioning

confidence: 99%

Progress with antiviral agents

Shugar

1974

FEBS Letters

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Immunosuppressive, antiviral and antitumor activities of cytarabine derivatives

Cited by 39 publications

References 26 publications

Comparison of the Antiviral Effects of 5-Methoxymethyl-deoxyuridine with 5-Iododeoxyuridine, Cytosine Arabinoside, and Adenine Arabinoside

Comparison of the Antiviral Effects of 5-Methoxymethyl-deoxyuridine with 5-Iododeoxyuridine, Cytosine Arabinoside, and Adenine Arabinoside

Effects of Adenine Arabinoside on Cellular Immune Mechanisms in Humans

Progress with antiviral agents

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