The aromatic-L-amino acid decarboxylase inhibitor carbidopa is selectivelycytotoxic 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 carcin oid hepatic metastases and adjacent normal liver (J, A. Gilbert et al,, Bio chem, Pharmacol., 50: 845-850, 1995), we identified one significant differe nce: the V-max,, of carcinoid AAAD was 50-fold higher than that in normal l iver. Here, we report Western and Northern analyses deterring large quantit ies of AAAD polypeptide and mRNA in human carcinoid primary as well as meta static tumors compared with normal surrounding tissues. To assess the feasi bility of targeting these high AAAD le, els for chemotherapy, AAAD inhibito rs carbidopa (alpha -methyl-dopahgdrazine), alpha -mononuoromcthyldopa (RFM D), and 3-hydroxybenzylhydrazine: (NSD-1015) were incubated (72 h) with NCI -H727 human lung carcinoid cells. Carbidopa and MFMD were lethal (IC50 = 29 +/- 2 muM and 56 +/- 6 muM, respectively); NSD-1015 had no effect on proli feration. 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 mum and 22 +/- 5 muM, respectively), Carbidopa (100 muM) decreased g rowth 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,vas NCI-H146 > NCI-H209 > SK-N-SH > NCI-H727, whereas A204, DU 145 , MCF7, and NCI-H4SD had no measurable activity. For lung tumor lines (carc inoid, two SCLC, and one large cell lung carcinoma), AAAD activity was corr elated with the potency of carbidopa-induced cytotoxicity. However, carcino id cell death was not solely attributable to complete inhibition of either AAAD activity or the serotonin synthetic pathway. In further evaluating pot ential applications of these findings with carbidopa, we determined that su blethal doses of carbidopa produced additive cytotoxic effects in carcinoid cells in combination with etoposide and cytotoxic synergy in SCLC cells wh en coincubated with topotecan.