Genetic risks of antiviral nucleoside analogues – a survey

doi:10.1016/S0166-3542(00)00139-X

Antiviral Research

Volume 49, Issue 2, 1 February 2001, Pages 55-74

https://doi.org/10.1016/S0166-3542(00)00139-X Get rights and content

Abstract

The available informations on the genotoxic effects in experimental systems of the antiherpesvirus nucleosides aciclovir, penciclovir, ganciclovir, brivudine and cidofovir as well as of the antiretrovirals zidovudine (AZT), lamivudine, zalcitabine (ddC), didanosine and stavudine are reviewed. Furthermore, data on carcinogenic activity of these drugs in laboratory rodents are compiled. Most nucleoside analogue antivirals induce chromosomal aberrations but are inactive in gene mutation assays. Carcinogenicity findings in mice and rats are variable but clearly positive for AZT and ddC. The possible mechanisms by which these agents may cause damage in the genetic information are still largely hypothetical, and experimental findings do not permit relevant extrapolations to the situation in man. There is no conclusive evidence that any of the drugs caused tumours in humans. The use of nucleoside analogues in antiviral therapy remains a pragmatic option that seems justified by risk/benefit assessment.

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).

References (89)

K.M. Ayers et al.
Nonclinical studies with zidovudine: genetic toxicity tests and carcinogenicity bioassays in mice and rats
Fund. Appl. Toxicol.
(1996)
G. Bubley et al.
Effects of (E)-5-(2-bromovinyl)-2′-deoxyuridine on the proliferation of herpes simplex virus type 1-transformed and thymidine kinase deficient mouse cells
Virology
(1983)
D. Clive et al.
Preclinical toxicology studies with acyclovir: genetic toxicity tests
Fund. Appl. Toxicol.
(1983)
E. De Clercq et al.
Mutagenic potential of anti-herpes agents
Life Sci.
(1986)
B.A. Diwan et al.
Multiorgan transplacental and neonatal carcinogenicity of 3′-azido-3′-deoxythymidine in mice
Toxicol. Appl. Pharmacol.
(1999)
E.R. Fearon et al.
A genetic model for colorectal tumorigenesis
Cell
(1990)
H.R. Glatt
Comparison of common gene mutation tests in mammalian cells in culture: a position paper of the GUM commission for the development of guidelines for genotoxicity testing
Mutat. Res.
(1994)
M. Gonzalez Cid et al.
Genotoxic activity of azidothymidine (AZT) in in vitro systems
Mutat. Res.
(1994)
D.J Grdina et al.
Protection against A2T-induced mutagenesis at the HGPRT locus in a human cell line by WR-151326
Int. J. Radiat. Oncol. Biol. Phys.
(1992)
P. Haynes et al.
Comparative in-vivo genotoxicity of antiviral nucleoside analogues; penciclovir, acyclovir, ganciclovir and the xanthine analogue, caffeine, in the mouse bone marrow micronucleus assay
Mutat. Res.
(1996)

C. Heidelberger et al.

Cell transformation by chemical agents – a review and analysis of the literature. A report of the U.S. Environmental Protection Agency Gene-Tox Program

Mutat. Res.

(1983)

A.L. Herbst

Behavior of estrogen-associated female genital tract cancer and its relation to neoplasia following intrauterine exposure to diethylstilbestrol (DES)

Gynecol. Oncol.

(2000)

B.A. Kunz et al.

Deoxyribonucleoside triphosphate levels: a critical factor in the maintenance of genetic stability

Mutat. Res.

(1994)

W.R. Mancini et al.

The relationship between incorporation of (E)-5-(2-bromovinyl)-2′-deoxyuridine into herpes simplex virus type 1 DNA with virus infectivity and DNA integrity

J. Biol. Chem.

(1983)

D.M. Maron et al.

Revised methods for the Samonella mutagenicity test

Mutat. Res.

(1983)

O.A. Olivero et al.

3′-azido-3′-deoxythymidine (AZT) transplacental perfusion kinetics and DNA incorporation in normal human placentas perfused with AZT

Mutat. Res.

(1999)

Y. Oshiro et al.

Genotoxic properties of (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU)

Fund. Appl. Toxicol.

(1992)

J.E. Reardon

Herpes simplex virus type 1 and human DNA polymerase interactions with 2′-deoxyguanosine 5′-triphosphate analogues

J. Biol. Chem.

(1989)

R. Reid et al.

Insertion and extension of acyclic, dideoxy, and ara nucleotides by herpesviridae, human α and human β polymerases

J. Biol. Chem.

(1988)

B.E. Schilling et al.

The nonclinical toxicologic profile of stavudine

Curr. Therapeut. Res.

(1995)

H.M. Shafik et al.

Recombinant human interferon beta ser protects against zidovudine-induced genetic damage in AIDS patients

Antiviral Res.

(1991)

M. Sorsa et al.

Monitoring of occupational exposure to cytostatic anticancer agents

Mutat. Res.

(1996)

H.E. Sussman et al.

Genotoxicity of 3′-azido-3′-deoxythymidine in the human lymphoblastoid cell line, TK6: relationships between DNA incorporation, mutant frequency, and spectrum of deletion mutations in HPRT

Mutat. Res.

(1999)

R. Thust et al.

Cytogenetic genotoxicity of antiherpes virostatics in Chinese hamster V79-E cells. I. Purine nucleoside analogues

Antiviral Res.

(1996)

W.E. Tucker et al.

Preclinical studies with acyclovir: carcinogenicity bioassays and chronic toxicity tests

Fund. Appl. Toxicol.

(1983)

G.E. Wright et al.

Deoxyribonucleotide analogs as inhibitors of DNA polymerases

Pharmacol. Ther.

(1990)

K.M. Ayers

Preclinical toxicology of zidovudine. An overview

Am. J. Med.

(1988)

M. Balter

Children become the first victims of fallout

Science

(1996)

J. Balzarini

Metabolism and mechanism of antiretroviral action of purine and pyrimidine derivatives

Pharmacy World Sci.

(1994)

J. Balzarini

Herpes simplex virus thymidine kinase gene-transfected tumor cells: sensitivity to antiherpetic drugs

Nucleosides Nucleotides

(1996)

J. Balzarini et al.

Increased sensitivity of thymidine kinase-deficient (TK⁻) tumor cell lines to the cell growth inhibitory effects of (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU) and related compounds

Anticancer Res.

(1986)

J. Balzarini et al.

Thymidylate synthase is the principal target enzyme for the cytostatic activity of (E)-5-(2-bromovinyl)-2′-deoxyuridine against murine mammary carcinoma (FM3A) cells transformed with the herpes simplex virus type 1 or type 2 thymidine kinase gene

Molec. Pharmacol.

(1987)

J. Balzarini et al.

Comparative cytostatic activity of different antiherpetic drugs against herpes simplex virus thymidine kinase gene-transfected tumor cells

Molec. Pharmacol.

(1994)

K. Birmingham

UN acknowledges HIV/AIDS as a threat to world peace

Nat. Med.

(2000)

C. Bonini et al.

HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia

Science

(1997)

J.M. Cameron

New antiherpes drugs in development

Rev. Med. Virol.

(1993)

J.J. Cassiman et al.

Sister chromatid exchange induced by anti-herpes drugs

Br. Med. J.

(1981)

A. Ciucci et al.

Mechanism of antiviral action of (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU): direct evidence with [¹⁴C]BVDU in herpes simplex virus-infected cells

Antivir. Chem. Chemother.

(1997)

D. Clive et al.

A double-blind, placebo-controlled cytogenetic study of oral acyclovir in patients with recurrent genital herpes

J. Infect. Dis.

(1991)

D.M. Coen

Molecular aspects of anti-herpesvirus drugs

Virology

(1992)

J.L. Cohen et al.

Suicide gene-mediated modulation of graft-versus-host diseases

Leuk. Lymphoma

(1999)

R. Combes et al.

Cell transformation assays as predictors of human carcinogenicity. The report and recommendations of ECVAM workshop 39

ATLA

(1999)

E.M. Connor et al.

Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group

N. Engl. J. Med.

(1994)

M. Culnane et al.

Lack of long-term effects of in utero exposure to zidovudine among children born to HIV-infected women. Pedriatric AIDS Clinical Trials Group Protocol 219/076 Teams

J. Am. Med. Assoc.

(1999)

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ReviewGenetic risks of antiviral nucleoside analogues – a survey

Abstract

Introduction

Section snippets

Bioassays for the detection of genetic damage

Data assessment

Possible mechanisms of induction of genetic damage by nucleoside antivirals

Iatrogenic carcinogenicity of antiviral drugs

Conclusions

Acknowledgements

Fund. Appl. Toxicol.

Virology

Fund. Appl. Toxicol.

Life Sci.

Toxicol. Appl. Pharmacol.

Cell

Mutat. Res.

Mutat. Res.

Int. J. Radiat. Oncol. Biol. Phys.

Mutat. Res.

Mutat. Res.

Gynecol. Oncol.

Mutat. Res.

J. Biol. Chem.

Mutat. Res.

Mutat. Res.

Fund. Appl. Toxicol.

J. Biol. Chem.

J. Biol. Chem.

Curr. Therapeut. Res.

Antiviral Res.

Mutat. Res.

Mutat. Res.

Antiviral Res.

Fund. Appl. Toxicol.

Pharmacol. Ther.

Preclinical toxicology of zidovudine. An overview

Am. J. Med.

Children become the first victims of fallout

Science

Metabolism and mechanism of antiretroviral action of purine and pyrimidine derivatives

Pharmacy World Sci.

Herpes simplex virus thymidine kinase gene-transfected tumor cells: sensitivity to antiherpetic drugs

Nucleosides Nucleotides

Increased sensitivity of thymidine kinase-deficient (TK−) tumor cell lines to the cell growth inhibitory effects of (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU) and related compounds

Anticancer Res.

Thymidylate synthase is the principal target enzyme for the cytostatic activity of (E)-5-(2-bromovinyl)-2′-deoxyuridine against murine mammary carcinoma (FM3A) cells transformed with the herpes simplex virus type 1 or type 2 thymidine kinase gene

Molec. Pharmacol.

Comparative cytostatic activity of different antiherpetic drugs against herpes simplex virus thymidine kinase gene-transfected tumor cells

Molec. Pharmacol.

UN acknowledges HIV/AIDS as a threat to world peace

Nat. Med.

HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia

Science

New antiherpes drugs in development

Rev. Med. Virol.

Sister chromatid exchange induced by anti-herpes drugs

Br. Med. J.

Mechanism of antiviral action of (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU): direct evidence with [14C]BVDU in herpes simplex virus-infected cells

Antivir. Chem. Chemother.

A double-blind, placebo-controlled cytogenetic study of oral acyclovir in patients with recurrent genital herpes

J. Infect. Dis.

Molecular aspects of anti-herpesvirus drugs

Virology

Suicide gene-mediated modulation of graft-versus-host diseases

Leuk. Lymphoma

Cell transformation assays as predictors of human carcinogenicity. The report and recommendations of ECVAM workshop 39

ATLA

Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group

N. Engl. J. Med.

Lack of long-term effects of in utero exposure to zidovudine among children born to HIV-infected women. Pedriatric AIDS Clinical Trials Group Protocol 219/076 Teams

J. Am. Med. Assoc.

Review
Genetic risks of antiviral nucleoside analogues – a survey

Increased sensitivity of thymidine kinase-deficient (TK⁻) tumor cell lines to the cell growth inhibitory effects of (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU) and related compounds

Mechanism of antiviral action of (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU): direct evidence with [¹⁴C]BVDU in herpes simplex virus-infected cells