Role of aldehyde dehydrogenase in the biological activity of spermine dialdehyde, a novel immunosuppressive/purging agent.
The antitumour and immunosuppressive activities of spermine dialdehyde (SDA), a synthetic, oxidized form of spermine, were examined using L1210 cell lines and murine bone marrow cells. SDA acted as a high affinity substrate for aldehyde dehydrogenase (ADH) derived from different sources, with kinetic profiles similar to other aldehyde substrates. The murine leukaemic, cyclophosphamide-resistant L1210/CPA cells, having high levels of intracellular ADH activity, were less sensitive to SDA compared to ADH deficient L1210/O cells as measured by [3H]-thymidine incorporation in proliferation studies. Furthermore, pretreatment of L1210/CPA cells with the ADH inhibitor, diethyl aminobenzaldehyde (DEAB), resulted in potentiation of the SDA response. Murine bone marrow cells were more resistant to SDA than splenic T cells. However, addition of DEAB to bone marrow cultures potentiated the sensitivity of progenitor cells to SDA, as measured by colony formation. The results indicate that levels of ADH in the target tissues would determine the potency of SDA and subsequently offer selectivity and specificity to the therapeutic potentials of this putative purging agent.
Kazmi
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SM
Biological Research Department, R. W. Johnson Pharmaceutical Research Institute at Ortho Pharmaceutical Canada Ltd, Don Mills, Ontario.
Li
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Koop
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Conant
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Lau
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D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000818:Animals; D001547:Benzaldehydes / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects / Q000201:enzymology; D001854:Bone Marrow Cells; D016465:Bone Marrow Purging; D002455:Cell Division / Q000187:drug effects*; D003520:Cyclophosphamide / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007939:Leukemia L1210; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D013096:Spermine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D014407:Tumor Cells, Cultured
D001547:Benzaldehydes; D007166:Immunosuppressive Agents; C050864:N,N'-bis(3-propionaldehyde)-1,4-diaminobutane; D013096:Spermine; D003520:Cyclophosphamide; D000444:Aldehyde Dehydrogenase