ethylglyoxal-bis(guanylhydrazone) and Carcinoma--Medullary

The significance of polyamines for the neoplastic proliferation and secretion of calcitonin (CT) and calcitonin-gene-related peptide (CGRP) by the human medullary thyroid carcinoma TT cell line was investigated. TT cells were cultured in vitro for 6 days with or without additions of pathway inhibitors of polyamine biosynthetic enzymes. Treatment of the cells with 1 mM of the specific L-ornithine decarboxylase (ODC) inhibitor DL-alpha-difluoromethylornithine (DFMO) resulted in a 97% decrease in ODC activity, lowered contents of putrescine (96%) and spermidine (85%) and cell proliferation rates (90%) along with a compensatory 15-fold increase in S-adenosyl-L-methionine decarboxylase (SAMDC) activity. DFMO treatment also led to a decrease in cellular content of CT (33%) and CGRP (26%), while the drug enhanced secretion of CT (31%) but depressed that of CGRP (26%), and elevated the ratio of CT to CGRP secreted into the medium by 74%. Ethylglyoxal bis(guanylhydrazone) (EGBG), a SAMDC inhibitor, at 100 microM evoked a similar reduction of cell proliferation and lowered the content of spermine by 81%. Furthermore, EGBG treatment caused a 34-fold increase in ODC activity and a subsequent 35-fold build-up of putrescine, but also seemed to stabilize SAMDC as evidenced by a highly enhanced SAMDC activity (approximately 200-fold) during enzyme assays in the absence of the inhibitor. EGBG exposure resulted in an increase in cellular CT content (110%) and secretion of the hormone (82%), while not affecting CGRP content or release.2+ EGBG effects were partially counteracted by DFMO.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosylmethionine Decarboxylase; Calcitonin; Calcitonin Gene-Related Peptide; Carcinoma, Medullary; Cell Division; Eflornithine; Humans; Mitoguazone; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitors; Polyamines; Putrescine; Spermidine; Spermine; Thyroid Neoplasms; Tumor Cells, Cultured