The aromatic-L-amino acid decarboxylase inhibitor carbidopa is selectively cytotoxic to human pulmonary carcinoid and small cell lung carcinoma cells.
The carcinoid tumor is an uncommon neuroendocrine neoplasm the hallmark of which is excessive serotonin production. In studying kinetics of tryptophan hydroxylase and aromatic-L-amino acid decarboxylase (AAAD) in human carcinoid hepatic metastases and adjacent normal liver (J. A. Gilbert et al, Biochem. Pharmacol., 50: 845-850, 1995), we identified one significant difference: the Vmax of carcinoid AAAD was 50-fold higher than that in normal liver. Here, we report Western and Northern analyses detecting large quantities of AAAD polypeptide and mRNA in human carcinoid primary as well as metastatic tumors compared with normal surrounding tissues. To assess the feasibility of targeting these high AAAD levels for chemotherapy, AAAD inhibitors carbidopa (alpha-methyl-dopahydrazine), alpha-monofluoromethyldopa (MFMD), and 3-hydroxybenzylhydrazine (NSD-1015) were incubated (72 h) with NCI-H727 human lung carcinoid cells. Carbidopa and MFMD were lethal (IC50 = 29 +/- 2 microM and 56 +/- 6 microM, respectively); NSD-1015 had no effect on proliferation. On exposure to other human tumor lines, carbidopa was lethal only to NCI-H146 and NCI-H209 small cell lung carcinoma (SCLC) lines (IC50 = 12 +/- 1 microM and 22 +/- 5 microM, respectively). Carbidopa (100 microM) decreased growth of (but did not kill) SK-N-SH neuroblastoma and A204 rhabdomyosarcoma cells and did not affect proliferation of DU 145 prostate, MCF7 breast, or NCI-H460 large cell lung carcinoma lines. The rank order of lines by AAAD activity was NCI-H146 > NCI-H209 > SK-N-SH > NCI-H727, whereas A204, DU 145, MCF7, and NCI-H460 had no measurable activity. For lung tumor lines (carcinoid, two SCLC, and one large cell lung carcinoma), AAAD activity was correlated with the potency of carbidopa-induced cytotoxicity. However, carcinoid cell death was not solely attributable to complete inhibition of either AAAD activity or the serotonin synthetic pathway. In further evaluating potential applications of these findings with carbidopa, we determined that sublethal doses of carbidopa produced additive cytotoxic effects in carcinoid cells in combination with etoposide and cytotoxic synergy in SCLC cells when coincubated with topotecan.
Gilbert
J A
JA
Department of Oncology, Research, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Frederick
L M
LM
Ames
M M
MM
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D002230:Carbidopa / Q000494:pharmacology*; D002276:Carcinoid Tumor / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007082:Ileum / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008854:Microscopy, Electron; D014407:Tumor Cells, Cultured
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D004791:Enzyme Inhibitors; D002230:Carbidopa