In-vitro effects of pemetrexed on bronchioloalveolar and adenocarcinoma of the lung

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Pemetrexed disodium (ALIMTA®, LY231514; Eli Lilly & Company, Indianapolis, IN, USA) is an antimetabolite that targets folate-requiring enzymes in the pyrimidine and purine synthesis pathways. Pemetrexed is an effective drug against mesothelioma, a cancer characterized by high levels of mRNA expression and protein production of the alpha folate receptor. mRNA microarray expression results of different types of lung cancers were evaluated to determine which histological types had high levels of alpha folate receptor and similar expression patterns of folate metabolism genes as mesothelioma. The expression patterns were studied to attempt to identify subsets of lung cancers which might respond more frequently to pemetrexed. The expression of the alpha folate receptor is 2.0 times higher in bronchioloalveolar carcinomas than mesotheliomas (p = 0.002), and 2.6 times that of other adenocarcinomas (p < 0.001). Hierarchical cluster analysis using a subset of genes in the folate metabolism pathway confirmed that the bronchioloalveolar carcinomas were most closely related to the mesotheliomas. This prompted studies of pemetrexed in different adenocarcinomas. 4 bronchioloalveolar cell carcinoma (NCI-H358, -H1650, -H1666, -H1781) and 5 adenocarcinoma (NCI-H23, -H441, -H2347, -H3122, -H3255) cell lines established from previously untreated patients have been exposed to pemetrexed in vitro. Pemetrexed inhibits growth by greater than 50% in a subset of the cell lines (NCI-H1666, NCI-H3255, NCI-H441) after 72 h exposure, as evaluated by the MTS assay (IC₅₀ 0.08, 0.05, 5.93 μM, respectively.) In addition, 72 h of treatment with 10 μM pemetrexed also caused growth inhibition in bronchioloalveolar carcinoma lines H358 (42%), H1650 (19%), H1666 (67%) and H1781 (20%), as well as in adenocarcinoma cell lines H23 (24%), H441 (55%), H2347 (10%), H3122 (40%) and H3255 (77%). In clonogenic assays, colony formation was successfully inhibited by 50% or more in H1666 and H441 cell lines, when treated with 0.1 μM- 10 μM pemetrexed (IC₅₀ 0.16 μM, 0.12 μM, respectively.) The H3255 cell line was not clonogenic at plating densities of less than 1200 cells/mL, and was thus not evaluated. The encouraging clinical information from treating patients with mesothelioma with pemetrexed and the in vitro information from studying adenocarcinomas should prompt further studies of pemetrexed in adenocarcinoma of the lung, including bronchioloalveolar cell carcinoma.