Analysis of cytotoxic effects of chemotherapeutic agents on lung and small intestinal neuroendocrine cell lines

Aim: Survival rates for gastrointestinal and bronchopulmonary neuroendocrine tumors (NETs) have not significantly altered in the past thirty years, while the icidence of these tumors continues to rise. Treatment protocols are based on data from clinical trials of non-neuroendocrine malignancies and no systematic analysis of chemotherapeutic agents has been undertaken in NET cell lines. Methods: The cytotoxic effects of ten common chemotherapeutic agents were assessed by MTT uptake and cell cycle distribution on three NET cell lines, NCI-H720 (atypical lung carcinoid), NCI-H727 (bronchopulmonary - typical carcinoid) and KRJ-I (small intestinal - typical carcinoid). Results: All three cell lines were sensitive to topetecan, NCI-H720 was most potently inhibited by topotecan (IC₅₀ 2.3 nM). Cyclophosphamide, bortezomib and paclitaxel all inhibited the cell cycle (P < 0.05). NCI-H727 also responded to topotecan (IC₅₀ 4.9 nM) and was also sensitive to doxorubucin liposomal (IC₅₀ 9.6 nM), cyclophosphamide (IC₅₀ 9.3 nM) and cisplatin (IC₅₀ 9.3 nM)(all P < 0.05) but resistant to sirolimus, gefitinib, paclitaxel, and doxorubicin hydrochloride. Borterzomib caused NCI-H727 cell cycle arrest (P < 0.05). KRJ-I responded to paclitaxel, topotecan, bortezomib, and cyclophosphamide (IC₅₀ 2-10 nM)(all P < 0.05) and poorly to doxorubucin liposomal. The KRJ-1 cell cycle was only altered by topotecan (G,/S arrest). Conclusion: Differences were evident in anti-proliferative responses between lung and intestinal NETs and between atypical and typical lung/ bronchial NET cell lines. This study provides evidence that individual (site and cell specific) NETs will respond differently to specific agents indicating that the use of specific agents for individual lesions is necessary to effectively treat NETs.