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Effect of polyamine deprivation on the survival of intracranial glioblastoma bearing rats.

It has previously been shown that systematic polyamine deprivation results in the almost complete inhibition of the growth of several solid tumors. The same polyamine deficient diet (containing antibiotics for the decontamination of the gastrointestinal tract, the ornithine decarboxylase inhibitor 2-(difluoromethyl)ornithine, and the polyamine oxidase inhibitor N1, N4-bis-(2,3-butadienyl)putrescine; "drug-containing polyamine deficient chow", DC-PDC) was applied for the first time to the treatment of rats with an intracranial tumor. Rats received intracortical grafts of C6 rat glioblastoma cells, and the length of their survival was determined. Treatment with DC-PDC, starting four days after tumor cell inoculation, significantly prolonged the median survival of the glioblastoma-bearing rats. The results underline the general growth inhibitory effect of systematic polyamine deprivation. Since the effect of polyamine restriction on tumor growth is reversible, combinations with cytotoxic drugs have to be found which exploit the changed functions of polyamine deficient tumor cells.

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PubMedDate not supplied

The gastrointestinal tract as polyamine source for tumor growth.

It has previously been demonstrated that decarboxylation of ornithine in tumors, and the oxidative splitting of N1-acetylspermidine in tumor and normal tissues, are important sources of putrescine. Both these sources are utilised by tumors and other tissues with a high demand for polyamines to ensure their polyamine requirement. Consequently, combined treatment of tumor-bearing animals with an inhibitor of ornithine decarboxylase (e.g. alpha-difluoromethylornithine) and polyamine oxidase (e.g. N,N'- bis-allenylputrescine) has an antitumoral effect superior to that of either drug alone. In the present work, it was demonstrated that the alimentary tract is a third important source of polyamines which maintains tumor growth. Gastrointestinal polyamines are of alimentary origin, and are also formed by aerobic and anaerobic microorganisms. They can be reduced by feeding a polyamine deficient diet together with antibiotics that are suitable for decontaminating the gastrointestinal tract. This treatment combined with the administration of the mentioned inhibitors of ornithine decarboxylase and polyamine oxidase completely prevents Lewis lung carcinoma from growing, and prolongs considerably the average life span of L1210 leukemia mice. The results of the polyamine analyses of tumors, leukemia cells and tissues are compatible with the notion that the effective blocking of the three main putrescine sources (intracellular decarboxylation of ornithine, formation of putrescine from N1-acetylspermidine, and the gastrointestinal tract) produces a very strong cytostatic effect. It is expected that the clinical efficacy of polyamine antimetabolites can be considerably improved by measures analogous to those applied in this pilot study.

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