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Detoxification of the Polyamine Analogue N¹-Ethyl-N¹¹-[(cycloheptyl)methy]-4,8-diazaundecane (CHENSpm) by Polyamine Oxidase¹

Departments of Radiation Oncology and Biochemistry [K. R. L., S. M., J. A. L., E. W. G.] and Microbiology and Immunology [C. M. P.], The University of Arizona, Arizona Cancer Center, Tucson, Arizona 85724; Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, Wayne State University, Detroit, Michigan 48202 [P. M. W.]; and Department of Oncology, The Johns Hopkins University Medical School, Baltimore, Maryland 21231 [R. A. C.]

Purpose: Analogues of the naturally occurring polyamines, alkylated on both terminal amines, are being developed as anticancer drugs. Because bisalkylated derivatives of putrescine (1,4-diaminobutane) are potent inhibitors of the flavin adenine dinucleotide-dependent polyamine oxidase (PAO), we asked whether PAO could detoxify synthetic bisalkylated polyamines with chain lengths longer than putrescine.

Experimental Design: We investigated the effects of one polyamine analogue in Chinese hamster ovary (CHO) and HCT116 human colon tumor-derived cells, which express dramatically different levels of PAO activity, and in these same cells treated with an inhibitor of PAO.

Results: Concentrations of N¹-ethyl-N¹¹-[(cycloheptyl)methyl]-4,8-diazaundecane (CHENSpm), ranging from 0.3 to 10 µM, caused growth arrest and reduced cell survival in HCT116 cells but not in CHO cells. This cell line-specific difference in CHENSpm toxicity was not attributable to differences in analogue uptake, because intracellular levels of the drug were similar in CHO and HCT116 cells treated with equivalent concentrations of CHENSpm in the presence of MDL 72,527, a specific inhibitor of PAO. The PAO inhibitor, in combination with CHENSpm, caused a significant increase in intracellular CHENSpm levels and increased growth inhibition and cell damage in CHO cells but not in HCT116 cells. CHO cells, but not HCT116 cells, produced two primary amine-containing metabolites from CHENSpm that were suppressed by MDL 72,527.

Conclusions: These data demonstrate that CHENSpm is detoxified in PAO-expressing CHO cells, but not in PAO-deficient HCT116 cells, by a mechanism yielding products containing free primary amine groups and implicate PAO as the detoxification enzyme. Because other studies suggest that PAO may be self-regulated in some tumors, differential expression of PAO may be the basis for selective toxicity of CHENSpm and other N-substituted polyamine analogues in certain cancers.

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