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DNA methylation in maternal, fetal and neonatal rat tissues following perinatal administration of procarbazine

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Summary

The cytostatic drug procarbazine has previously been shown to be a potent transplacental neurotropic carcinogen in rats. Following a single IP administration of (14C-methylprocarbazine (110 mg/kg) on day 22 of gestation, methylation products with cellular DNA were determined in fetal and maternal rat organs. The concentration of the major adduct N7-methylguanine was highest in the maternal liver (224 μmol/mol guanine). Fetal and nonhepatic maternal tissues exhibited significantly lower levels, but differed little from each other. In brain, lung, intestines, and placenta the O 6-methylguanine/N7-methylguanine ratio was close to 0.11, indicating that procarbazine, like other methylating carcinogens, initiates malignant transformation via methyldiazonium hydroxide as the ultimate reactant. Following a single dose of (14C-methyl)procarbazine to newborn animals, methylpurine values were 30–60 times lower than after prenatal administration. This suggests that DNA alkylation in nonhepatic tissues occurs by systemic distribution of a proximate carcinogen formed in the adult rat liver.

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References

  • Bacci M, Cavaliere A, Fratini D (1982) Lung carcinogenesis by procarbazine chlorate in BALB/c mice. Carcinogenesis 3:71–73

    Google Scholar 

  • Deckers C, Deckers-Passau L, Maisin J, Gauthier JM, Mace F (1974) Carcinogenicity of procarbazine. Z Krebsforsch 81:79–84

    Google Scholar 

  • Druckrey H, Preussmann R, Ivankovic S (1967) Organotrope carcinogene Wirkungen bei 65 verschiedenen N-Nitroso-Verbindungen an BD-Ratten. Z Krebsforsch 69:103–201

    Google Scholar 

  • Dunn DL, Lubet RA, Prough RA (1979) Oxidative metabolism of N-isopropyl-α-(2-methylhydrazino)-p-toluamide hydrochloride (procarbazine) by rat liver microsomes. Cancer Res 39:4555–4563

    Google Scholar 

  • Goodmann LS, Gilman A (1980) The pharmacological basis of therapeutics, 5th edn. Macmillan, New York

    Google Scholar 

  • International Agency for Research on Cancer (1981) IARC Monographs on the evaluation of the carcinogenic risk of chemicals to humans. Some antineoplastic and immunosuppressive agents. IARC Monographs 26:311–339

    Google Scholar 

  • Ivankovic S (1968) Transplacentare Erzeugung maligner Tumoren des Nervensystems. I. Äthyl-nitroso-harnstoff (ÄNH) an BD IX-Ratten. Z Krebsforsch 71:320–360

    Google Scholar 

  • Ivankovic S (1972) Erzeugung von Malignomen bei Ratten nach transplazentarer Einwirkung von N-Isopropyl-α-2-(methyl-hydrazino)-p-toluamid HCl. Arzneimittelforsch 22:905–907

    Google Scholar 

  • Ivankovic S (1975) Praenatale Cancerogenese. In: Altmann H-W, Büchner F, Cottier H (Hrsg) Handbuch der allgemeinen Pathologie, vol VI/7. Springer, Berlin New York, pp 941–1002

    Google Scholar 

  • Kelly MG, O'Gara RW, Gadekar K, Yancey ST, Oliverio VT (1964) Carcinogenic activity of a new antitumor agent, N-isopropyl-α-(2-methylhydrazino)-p-toluamide, hydrochloride (NSC-77213). Cancer Chemother Rep 39:77–80

    Google Scholar 

  • Kelly MG, O'Gara RW, Yancey ST, Botkin C (1968) Induction of tumors in rats with procarbazine hydrochloride. J Natl Cancer Inst 40:1027–1051

    Google Scholar 

  • Kelly MG, O'Gara RW, Yancey ST, Gadekar K, Botkin C, Oliverio VT (1969) Comparative carcinogenicity of N-isopropyl-α-(2-methylhydrazino(-p-toluamide HCl (procarbazine hydrochloride). Its degradation products, other hydrazines, and isonicotine acid hydrazide. J Natl Cancer Inst 42:337–344

    Google Scholar 

  • Kleihues P, Lantos PL, Magee PN (1976) Chemical carcinogenesis in the nervous system. Int Rev Exp Pathol 15:153–232

    Google Scholar 

  • Kleihues P, Cooper HK, Buecheler J, Kolar GF, Diessner H (1979a) Mechanism of perinatal tumor induction by neuro-oncogenic alkylnitrosoureas and dialkylaryltriazenes. Natl Cancer Inst Monogr 51:227–231

    Google Scholar 

  • Kleihues P, Doerjer G, Keefer LK, Rice JM, Roller PP, Hodgson RM (1979b) Correlation of DNA methylation by methyl (acetoxymethyl)nitrosamine with organ-specific carcinogenicity in rats. Cancer Res 39:5136–5140

    Google Scholar 

  • Kreis W (1970) Metabolism of an anticoplastic methylhydrazine derivative in a P815 mouse neoplasm. Cancer Res 30:82–89

    Google Scholar 

  • Lee IP, Dixon RL (1978) Mutagenicity carcinogenicity and teratogenicity of procarbazine. Mutat Res 55:1–14

    Google Scholar 

  • Margison GP, Kleihues P (1975) Chemical carcinogensis in the nervous system. Preferential accumulation of O 6-methylguanine in rat brain deoxyribonucleic acid during repetitive administration of Nethyl-N-nitrosourea. Biochem J 148:521–525

    Google Scholar 

  • O'Gara RW, Adamson RH, Kelly MG, Dalgard DW (1971) Neoplasms of the hematopoietic system in nonhuman primates: report of one spontaneous tumor and two leukemias induced by procarbazine. J Natl Cancer Inst 46:1121–1130

    Google Scholar 

  • Pegg AE (1984) Properties of the O 6-alkylguanine-DNA repair system of mammalian cells. IARC Sci Publ (in press)

  • Pegg AE, Wiest L, Foote RS, Mitra S, Perry W (1983) Purification and properties of O 6-methylguanine-DNA transmethylase from rat liver. J Biol Chem 258:2327–2333

    Google Scholar 

  • Reed DJ (1975) Procarbazine. In: Sartorelli AC, Johns DG (eds) Antineoplastic and immunosuppressive agents, part II. Springer, New York, pp 747–765

    Google Scholar 

  • Shiba DA, Weinkam RJ, Levin VA (1979) Metabolic activation of procarbazine: activity of the intermediates and effects of pre-treatment. Proc Am Assoc Cancer Res 20:139

    Google Scholar 

  • Sieber SM, Correa P, Dalgard DW, Adamson RH (1978) Carcinogenic and other adverse effects of procarbazine in nonhuman primates. Cancer Res 38:2125–2134

    Google Scholar 

  • Weinkam RJ, Shiba DA (1978) Metabolic activation of procabazine. Life Sci 22:937–946

    Google Scholar 

  • Weisburger JH, Griswold DP, Prejean JD, Casey AE, Wood HB, Weisburger EK (1975) The carcinogenic properties of some of the principal drugs used in clinical cancer chemotherapy. Recent Results Cancer Res 52:1–17

    Google Scholar 

  • Wiebkin P, Prough RA (1980) Oxidative metabolism of N-isopropyl-α-(2-methylazo)-p-toluamide (azoprocarbazine) by rodent liver microsomes. Cancer Res 40:3524–3529

    Google Scholar 

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Dedicated to Professor Hermann Druckrey on the occasion of his 80th birthday

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Wiestler, O.D., Kleihues, P., Rice, J.M. et al. DNA methylation in maternal, fetal and neonatal rat tissues following perinatal administration of procarbazine. J Cancer Res Clin Oncol 108, 56–59 (1984). https://doi.org/10.1007/BF00390973

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