Summary
We have developed a beagle dog model to study the pharmacology and toxicology of anticancer drugs administered through the 3rd or lateral ventricles. A Foltz-type reservoir was implanted SC and connected by tube into a cerebral ventricle. Drugs were administered directly into the reservoir; CSF sampling of drugs administered into the ventricle was achieved directly by tapping the reservoir or by percutaneous puncture of the cisterna magna. In the current study, we evaluated the CSF pharmacokinetics and CNS toxicity of two inhibitors of polyamine metabolism, α-difluoromethylornitine (DFMO) and methylglyoxal bisguanylhydrazone (MGBG). Both drugs were judged too toxic to justify intrathecal or intraventricular studies with these agents in patients.
Similar content being viewed by others
References
Abeloff MD, Slavik M, Luk GD, Griffin CA, Hermann J, Blanc O, Sjoerdsma A, Baylin SB (1983) Phase I clinical and pharmacokinetic studies of α-difluoromethylornithine (DFMO). Proc Soc Clin Oncol 2:22
Bartholeyns J, Koch-Weser J (1981) Effects of α-difluoromethylornithine alone and in combination with adriamycin or vindesine on L1210 leukemia in mice, EMT6 solid tumors in mice, and solid tujors induced by injection of hepatoma tissue culture cells in rats. Cancer Res 41:5158
Gibaldi M (1977) Biopharmaceutics and clinical pharmacokineties. Lea & Febiger, Philadelphia, p 80
Grove J, Fozard JR, Mamont PS (1981) Assay of alpha-difluoromethylornithine in body fluids and tissues by automatic amino acid analysis. J Chromatogr 223:409
Haegele K, Alken R, Grove J, Schechter PJ, Koch-Weser J (1981) Kinetics of alpha-difluoromethylornithine: An irreversible inhibitor of ornithine decarboxylase. Clin Pharmacol Ther 2:210
Hung DT, Deen DF, Seidenfield J, Marton LJ (1981) Sensitization of 9L rat brain gliosarcoma cells to 1,3-bis(2-chloroethyl)-1-nitrosourea by alpha-difluoromethylornithine, an ornithine decarboxylase inhibitor. Cancer Res 41:2783
Levin VA, Csejtey J, Byrd DJ (1983) Brain, CSF, and tumor pharmacokinetics of α-difluoromethylornithine in rats and dogs. Cancer Chemother Pharmacol 10:196
Luk GD, Goodwin G, Marton LJ, Baylin SB (1981) Polyamines are necessary for the survival of human small-cell lung carcinoma in culture. Proc Natl Acad Sci USA 78:2355
Mamont PS, Duchesne MC, Joder-Ohlenbusch AM, Grove J (1978) Effects of ornithine decarboxylase inhibitors on cultured cells. In: Seiler N, Jung MJ, Koch-Weser J (eds) Enzyme-activated irreversible inhibitors. Elsevier-North Holland, Amsterdam, p 43
Marton LJ (1984) Polyamines and cancer therapy. Ann Int Med (in press)
Marton LJ, Levin VA, Hervatin S, Koch-Weser J, McCann P, Sjoerdsma A (1981) Potentiation of the antitumor therapeutic effect of 1,3-bis(2-chloroethyl)-1-nitrosourea by α-difluoromethylornithine, an ornithine decarboxylase inhibitor. Cancer Res 41:4426
Marton LJ, Oredsson SM, Hung DT, Deen DF (1983) Effects of polyamine depletion on the cytoxicity of cancer chemotherapeutic agents. In: Bachrach U, Kaye A, Chayen R (eds) Advances in polyamine research. Raven Press, New York, p 33
Prakash NJ, Schechter PJ, Grove J, Koch-Weser J (1978) Effect of α-difluoromethylornithine an enzyme-activated irreversible inhibitor of ornithine decarboxylase on L1210 leukemia in mice. Cancer Res 38:3059
Rosenblum MG, Stewart DJ, Yap BS, Leavens M, Benjamon RS, Loo TL (1981) Penetration of methylglyoxal bis(guanylhydrazone) into intracerebral tumors in humans. Cancer Res 41:459
Seppanen P, Alhonen-Hongisto L, Siimes M, Janne J (1980) Quantitation of methylglyoxal bis(guanylhydrazone) in blood plasma and leukemia cells of patients receiving the drug. Int J Cancer 26:571
Warrell RP, Burchenal JH (1983) Methylglyoxal-bis-(guanylhydrazone) (methyl-GAG): Current status and future prospects. J Clin Oncol 1:52
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Levin, V.A., Byrd, D., Campbell, J. et al. CNS toxicity and CSF pharmacokinetics of intraventricular DFMO and MGBG in beagle dogs. Cancer Chemother. Pharmacol. 13, 200–205 (1984). https://doi.org/10.1007/BF00269029
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00269029