Normal and malignant human urothelium: in vitro response to blockade of polyamine synthesis and interconversion.
To assess the effect of polyamine blockade on urinary epithelium, growth of normal human urothelial cell cultures and human transitional cell carcinoma (TCC) cell lines in the presence of various inhibitors of polyamine synthesis was evaluated. All four human TCC cell lines tested were quite sensitive to the specific inhibitor of ornithine decarboxylase, alpha-difluoromethylornithine (DFMO), requiring less than or equal to 1.0 mM DFMO to double generation time. Alternatively, all three human urothelial cultures tested required 5-20-fold higher DFMO concentrations to achieve similar growth inhibition. The inhibitory effect of DFMO on TCC was found to act synergistically with that of the inhibitor of S-adenosylmethionine decarboxylase, methylglyoxal bis(guanylhydrazone), and additively with that of recombinant beta-serine interferon. Addition of individual polyamines entirely prevented the inhibitory effects of DFMO and/or methylglyoxal bis(guanylhydrazone) but not that of beta-serine interferon. It appears that inhibition of polyamine synthesis and/or interconversion holds promise in the management of TCC and that the in vitro model described will be of value in investigating such clinical applications.
Messing
E M
EM
Department of Surgery, University of Wisconsin School of Medicine, Madison 53792.
Hanson
P
P
Reznikoff
C A
CA
D002295:Carcinoma, Transitional Cell / Q000188:drug therapy / Q000473:pathology*; D000518:Eflornithine / Q000494:pharmacology*; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology; D000068556:Interferon beta-1a; D000068576:Interferon beta-1b; D016899:Interferon-beta; D008935:Mitoguazone / Q000494:pharmacology; D009955:Ornithine Decarboxylase / Q000096:biosynthesis; D011073:Polyamines / Q000096:biosynthesis* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D001743:Urinary Bladder / Q000187:drug effects*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000473:pathology*
D007370:Interferon Type I; D011073:Polyamines; D011994:Recombinant Proteins; D000068576:Interferon beta-1b; D016899:Interferon-beta; D009955:Ornithine Decarboxylase; D008935:Mitoguazone; D000068556:Interferon beta-1a; D000518:Eflornithine