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.