Abstract
Several virustatic agents are known to be teratogenic in laboratory animals. Since routinely performed in vivo studies do not always offer the best conditions to detect the teratogenic potential of a drug, we used a combined in vivo/in vitro approach for comparative studies on the prenatal toxicity of five nucleoside analogues. Rat embryos were exposed for 48 h to various concentrations of vidarabine-phosphate (VAP), ganciclovir (GCV), 2′,3′-dideoxyadenosine (ddA), 2′,3′-dideoxycytidine (ddC) and zidovudine (= azidothymidine, AZT) in a whole-embryo culture system. The steepness of the concentration-response curves as well as the induced abnormality pattern (head, neural tube, shape) were similar for these compounds. However, a wide range in embryotoxic potency was observed: VAP was the most potent compound (100% abnormal embryos at 25 μM) in this in vitro system, while AZT showed the lowest potency to interfere with normal embryonic development (40% abnormal embryos at 3000 μM). In addition to these experiments we treated rats on day 10 of gestation with three s.c. injections (8 a.m.; 12 a.m.; 4 p.m.) of 200 mg of each drug/kg body wt. The embryos were evaluated on day 11.5 of gestation, i.e. at a time of development corresponding to the developmental stage at the end of the whole-embryo culture. The same criteria were used as during the in vitro studies for the evaluation of these in vivo exposed embryos. With VAP and GCV we obtained similar results with both exposure routes (in vitro and in vivo), while no abnormalities were detectable with the other compounds after exposure in utero. When the results from the in vitro and in vivo studies are compared with data of similar experiments conducted in our laboratory with the nucleoside analogue aciclovir (ACV) under identical conditions (Klug et al. 1985 a; Stahlmann et al. 1988), the following conclusions can be drawn: under in vitro conditions VAP showed the highest potential of the virustatics to interfere with embryonic development, the toxic potential of AZT was surprisingly low. Under our experimental in vivo conditions ACV reveals the highest teratogenic potential, whereas ddC, ddA, and AZT exhibited an obviously lower toxicity.
Similar content being viewed by others
Abbreviations
- VAP:
-
vidarabine-phosphate
- GCV:
-
ganciclovir
- ddA:
-
2′,3′-dideoxyadenosine
- ddC:
-
2′,3′-dideoxycytidine
- AZT:
-
zidovudine (= azidothymidine)
- ACV:
-
aciclovir, acicloguanosine
- WEC:
-
whole-embryo culture
References
Brown NA, Fabro S (1981) Quantitation of rat embryonic development in vitro: a morphological scoring system. Teratology 24: 65–78
Chahoud I, Stahlmann R, Bochert G, Dillmann I, Neubert D (1988) Gross-structural defects in rats after aciclovir application on day 10 of gestation. Arch Toxicol 62: 8–14
Cockroft DJ (1977) Post implantation embryo culture. In: Neubert D, Merker HJ, Kwasigroch TE (eds) Methods in prenatal toxicology. Georg Thieme Publ, Stuttgart, pp 231–240
Crumpacker CS (1989) Molecular targets of antiviral therapy. N Engl J Med 321: 163–172
Dayan AD, Anderson D (1988) Toxicity of antiviral compounds. In: Field HJ (ed) Antiviral agents. CRC Press, Boca Raton, Florida 1: 111–125
Fischl MA, Richmann DD, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, Leedom JM, Groopman JE, Mildvan D, Schooley RT, Jackson GG, Durack DT, King D and the AZT Collaborative Working Group (1987) The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. N Engl J Med 317: 185–197
Greene JA, Ayers KM, de Miranda P, Tucker WE Jr. (1990) Postnatal survival in Wistar rats following oral dosage with Zidovudine on gestation day 10. Fundam Appl Toxicol 15: 201–206
Haertle T, Carrera CJ, Wasson DB, Sowers LC, Richmann DD, Carson DA (1988) Metabolism and anti-human immunodeficiency virus-1 activation of 2-halo-2′,3′-dideoxyadenosine derivatives. J Biol Chem 263: 5870–5875
Henderson DK, Gerberding JL (1989) Prophylactic zidovudine after occupational exposure to the human immunodeficiency virus. An interim analysis. J Infect Dis 160: 321–326
Klecker RW, Collins JM, Yarchoan R (1987) Plasma and cerebrospinal fluid pharmacokinetics of 3′-azido-3′-deoxythymidine: a novel pyrimidine analog with potential application for the treatment of patients with AIDS and related diseases. Clin Pharmacol Ther 41: 407–412
Klug S, Lewandowski C, Blankenburg G, Merker H-J, Neubert D (1985 a) Effect of aciclovir on mammalian embryonic development in culture. Arch Toxicol 58: 89–96
Klug S, Lewandowski C, Neubert D (1985b) Modification and standardization of the culture of early postimplantation embryos for toxicological studies. Arch Toxicol 58: 84–88
Klug S, Lewandowski C, Stahlmann R, Neubert D (1987) Teratogenic potential of two virustatic agents in the rat: comparison of in vitro and in vivo data. Teratology 36: 27A
Langtry HD, Campoli-Richards DM (1989) Zidovudine: a review of its pharmacodynamic and pharmacokinetitc properties, and therapeutic efficacy. Drugs 37: 408–450
Moore Jr HL, Szczeck GM, Rodwell DE, Kapp Jr RW, de Miranda P, Tucker Jr WE (1983) Preclinical toxicology studies with aciclovir: teratologic, reproductive and neonatal tests. Fund Appl Toxicol 3: 560–568
Neubert D, Blankenburg G, Chahoud I, Franz G, Herken R, Kastner M, Klug S, Kröger J, Krowke R, Lewandowski C, Merker H-J, Schulz T, Stahlmann R (1986) Results of in vivo and in vitro studies for assessing prenatal toxicity. Environ Health Perspect 70: 89–103
New DAT (1978) Whole-embryo culture and the study of mammalian embryos during organogenesis. Biol Rev 53: 81–122
O'Brien JJ, Campoli-Richards DM (1989) Aciclovir — an updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. Drugs 37: 233–309
Sharpe AH, Jaenisch R, Ruprecht RM (1987) Retroviruses and mouse embryo: a rapid model for neurovirulence and transplacental antiviral therapy. Science 235: 1671–1674
Stahlmann R, Klug S, Lewandowski C, Bochert G, Chahoud I, Rahm U, Merker H-J, Neubert D (1988) Prenatal toxicity of aciclovir in rats. Arch Toxicol 61: 468–479
Verheyden JPH (1988) Evolution of therapy for cytomegalovirus infection. Rev Infect Dis 10: 477–489
Volberding PA, Lagakos SW, Koch MA, Pettinelli C, Myers MW, Booth DK, Balfour HH, Reichmann RC, Bartlett JA, Hirsch MS, Murphy RL, Hardy WD, Soeiro R, Fischl MA, Bartlett JG, Merigan TC, Hyslop NE, Richman DD, Valentine FT, Corey L and the AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases (1990) Zidovudine in asymptomatic human immunodeficiency virus infection. N Engl J Med 322: 942–949
Whitley R, Alford C, Hess F, Buchanan R (1980) Vidarabine: a preliminary review of its pharmacological properties and theapeutic use. Drugs 20: 267–282
Whitley RJ, Alford CA, Hirsch MS, Schooley RT, Luby JP, Aoki FY, Hanley D, Nahmias AJ, Soong S-J (1986) NIAID Collaborative Antiviral Study Group, Vidarabine versus aciclovir therapy in herpes simplex encephalitis. N Engl J Med 314: 144–149
Zimmermann TP, Mahony WB, Prus KL (1987) 3-Azido-3′-deoxythysmidine: an unusual nucleoside analogue that permeates the membrane of human erythrocytes and lymphocytes by non-facilitated diffusion. J Biol Chem 262: 5748–5754
Author information
Authors and Affiliations
Additional information
Dedicated to Professor Gerhard Zbinden on the occasion of his retirement
Rights and permissions
About this article
Cite this article
Klug, S., Lewandowski, C., Merker, HJ. et al. In vitro and in vivo studies on the prenatal toxicity of five virustatic nucleoside analogues in comparison to aciclovir. Arch Toxicol 65, 283–291 (1991). https://doi.org/10.1007/BF01968962
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01968962