The
carcinoid tumor, an uncommon neuroendocrine
neoplasm, is associated with
serotonin overproduction as is more common
small cell lung carcinoma (SCLC). alpha-Methyl-dopahydrazine (
carbidopa), an inhibitor of the
serotonin synthetic
enzyme aromatic-L-amino acid decarboxylase, proved lethal to NCI-H727 lung
carcinoid cells as well as NCI-H146 and NCI-H209 SCLC cells, but not to five other human tumor cell lines of differing origins [Gilbert JA, Frederick LM, Ames MM. The
aromatic-L-amino acid decarboxylase inhibitor
carbidopa is selectively cytotoxic to human pulmonary
carcinoid and
small cell lung carcinoma cells. Clin.
Cancer Res. 2000;6:4365-72]. The mechanism of
carbidopa cytotoxicity remained an unanswered question. We present data here that incubation of the
catechol carbidopa (100 microM) in RPMI and DMEM
culture media yielded molar equivalents of
hydrogen peroxide (H2O2) within 2-4 h. Alkaline elution studies revealed
carbidopa-dependent single-strand DNA breaks in sensitive
carcinoid cells comparable to those induced by similar concentrations of H2O2. Neither compound induced significant DNA damage in
carbidopa-resistant NCI-H460 large cell lung
carcinoma cells. Furthermore, when
carbidopa was incubated with a variety of
tumor cell types, not only were decreased media H2O2 concentrations detected in the presence of cells, but cell lines least sensitive to
carbidopa degraded exogenous H2O2 more rapidly than did sensitive cells. Implicated in these studies,
pyruvate degraded H2O2 in RPMI in a dose- and time-dependent manner and reversed
carbidopa-induced cytotoxicity to
carcinoid cells. Extracellular
pyruvate levels produced per h by resistant large cell lung
carcinoma cells averaged four-fold that of sensitive
carcinoid cells plated at equal density (24 h time course). Finally,
carbidopa exposure (100 microM, 24 h) depleted extracellular
pyruvate from sensitive
carcinoid cells, but reduced
pyruvate levels from resistant NCI-H460 cells less than 17%.