PubMed · 4211508
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C P Chang. 1974. [Methyldopa and levodopa].. https://pubmed.ncbi.nlm.nih.gov/4211508/
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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%.
The aromatic L-amino acid decarboxylase (AAAD) enzyme is significantly upregulated in neuroendocrine tumors and, thus, would be a good target for PET imaging agents. Alpha-fluoromethyl-DOPA (FMDOPA) is one of the most potent irreversible AAAD inhibitor and its non-catechol derivative, alpha-fluoromethyl-m-tyrosine (FMmT), is a promising AAAD imaging agent. We synthesized FMmT and its direct electrophilic fluorination provided a mixture of products identified by NMR analysis after HPLC purification as 6-fluoro-, 2-fluoro- and 2,6-difluoro-derivatives of FMmT. Using rat striatal homogenates, alpha-fluoromethyl-6-fluoro-m-tyrosine (FM-6-FmT) was found to have AAAD inhibitory activity comparable to that of FMDOPA. Electrophilic radiofluorination of FMmT using [18F]AcOF gave 18F labeled 6-fluoro-, 2-fluoro- and 2,6-difluoro-FMmT derivatives in 22.0%, 21.9% and 8.5% radiochemical yields, respectively. Based on its proposed mechanism of inhibition, FM-6-[18F]FmT is expected to irreversibly bind to AAAD and, hence, could be used as a PET agent to image tumors of endocrine origin containing high concentrations of AAAD. Since FM-6-FmT lacks the catechol moiety, it is expected to be better than FMDOPA since it is not a substrate for catechol-O-methyltransferase.
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.