ReviewGenetic risks of antiviral nucleoside analogues – a survey
Introduction
Vaccination is the most efficient way for the control and therapy of virus diseases. But for many viral infections vaccines are not available so far, and the only hitherto existing alternative are drugs that inhibit virus replication without extensively impairing host cell physiology by taking advantage of subtle differences between viral and cellular metabolism. Nucleoside analogues belong to this class of drugs and play a prominent role in the therapy of herpesvirus and HIV infections. The ultimately active metabolites of most nucleoside analogues are their triphosphates. In case of antiherpes nucleosides virus-encoded nucleoside kinases, e.g. thymidine kinase of HSV or VZV, or a protein kinase of CMV, accomplish the formation of the analogue monophosphates that are metabolised to the respective triphosphates by cellular kinases, whereby the monophosphorylation step appears to be rate-limiting, i.e. a major factor of antiviral selectivity of antiherpes drugs (for reviews see Cameron (1993), Kulikowski (1994), Darby (1995) and De Clercq (1995)). On the other hand, retroviruses do not encode their own nucleoside kinases and antiretrovirals are phosphorylated to triphosphates by cellular enzymes. In both cases, the triphosphates formed interact with either the virus-encoded DNA polymerase of herpesviruses or with the reverse transcriptase of retroviruses by competition with natural nucleoside triphosphates and/or substrate inhibition. The much lower Ki values of analogue triphosphates for viral polymerases as compared to cellular DNA polymerases are another component of the antiviral selectivity of these drugs (Wright and Brown, 1990, Coen, 1992).
Antiviral nucleoside analogues, similar to other drugs, may cause a plethora of acute side effects which are mostly controllable or may lead to discontinuance of the therapy and replacement by other drugs. Chronic toxicity, above all potential carcinogenicity, is of more concern. Toxicity of antiretrovirals recently even became a political issue in South Africa with respect to zidovudine (AZT) treatment of pregnant women in order to prevent vertical HIV transmission (Birmingham, 2000).
Although any conclusive evidence for human carcinogenicity of antiviral nucleosides is lacking, they are reputed to be carcinogens. Presumably, this assumption came from the fact that the mode of action of these drugs relies on interference with nucleic acid metabolism and, thus, hereditary changes in the genetic information of the host organism might be suspected. In this survey, we compile what is known so far on this topic with regard to the majority of licensed antiherpes and antiretroviral nucleosides (Fig. 1). Unfortunately, many of the findings that were acquired for drug approval by the manufacturers have not been published as original data. In these cases, we had to rely on informations given in the Physicians’ Desk Reference (2000).
Altogether, the overview shows that great gaps still exist in our knowledge of possible genetic risks of antiviral nucleoside analogues and, if genotoxic effects have been observed in diverse systems, how to explain them in mechanistic terms.
Section snippets
Bioassays for the detection of genetic damage
About a hundred tests for genotoxic activity have been described during the last three or four decades. The primary aim of these assays was to replace the expensive, laborious and time-consuming animal experiments, especially those for carcinogenicity. As outlined below, these expectations were not fulfilled, nevertheless a battery of screening assays for genotoxicity became an established constituent of preclinical toxicology without which novel drugs cannot be approved nowadays. In the
Data assessment
Fig. 1 shows the structure of licensed nucleoside analogue drugs with antiherpes (aciclovir (ACV), penciclovir, ganciclovir, brivudine and cidofovir) or antiHIV (AZT, lamivudine, zalcitabine, didanosine, and stavudine) activity for which findings presented in original publications or reviewed in the Physicians’ Desk Reference (2000) seemed sufficient for an assessment of genotoxic and/or carcinogenic activity. These data are summarized in Table 1. Where positive results have been reported, the
Possible mechanisms of induction of genetic damage by nucleoside antivirals
The mechanisms causing genetic alterations in mammalian cells by antiviral nucleoside analogues are still essentially unknown. While most chemical mutagens are converted, via metabolisation or spontaneous hydrolysis, to highly reactive electrophilic intermediates that bind to nucleophilic sites in DNA, thus forming adducts which impair ordinary base pairing and, in consequence, lead to alterations of base sequences, such a mode of action is irrelevant for nucleoside analogues. The antiviral
Iatrogenic carcinogenicity of antiviral drugs
The findings listed in Section 3 of this survey suggest that, perhaps with a few exceptions, neither of the drugs showed dramatic yields in the induced genotoxic effects in diverse bioassays or in cancer induction in animals. The crucial question is how to extrapolate experimental findings to the situation in patients. In quantitative and even in qualitative terms, neither genotoxicity nor carcinogenicity are intrinsic and independent properties of chemical compounds. They depend on
Conclusions
As discussed above, hitherto existing data of genotoxic and/or carcinogenic properties of antiviral nucleoside analogues do not allow a reliable assessment of the long-term genetic risk posed by these drugs in man. Whereas ACV, PCV/FCV, lamivudine (3TC), didanosine (ddI) and D4T were inactive or gave borderline effects in most experimental systems, AZT and ddC were clearly carcinogenic in mice and, partially, in rats. Furthermore, it has been shown that GCV is an extremely potent cytogenetic
Acknowledgements
We thank Prof. Dr. B. Kaina, University of Mainz, for helpful discussions. Our research was supported by the “Deutsche Forschungsgemeinschaft” (Grant TH 670/1-3).
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