J. Cancer Mol. 4: 47-54, 2008
[Research Paper]
Analysis of Cytotoxic Effects of Chemotherapeutic Agents
on Lung and Small Intestinal Neuroendocrine Cell Lines
Jan
Bornschein, Mark Kidd, Maximilian V. Malfertheiner, Ignat Drozdov,
Roswitha Pfragner, and Irvin M. Modlin
Gastrointestinal Pathobiology Research Group, Yale University School of
Medicine, New Haven, Connecticut, USA [J. Bornschein; M. Kidd; M. V.
Malfertheiner; I. Drozdov; I. M. Modlin]; Institute of Pathophysiology,
Centre for Molecular Medicine, Medical University of Graz, Austria [R.
Pfragner]
Abstract:
AIM:
Survival rates for gastrointestinal and bronchopulmonary neuroendocrine
tumors (NETs) have not significantly altered in the past thirty years,
while the incidence 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 topotecan. 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
8.3 nM)(all P < 0.05) but resistant to sirolimus, gefitinib,
paclitaxel, and doxorubicin hydrochloride. Bortezomib 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 (G1/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.
(Keywords: neuroendocrine tumor;
bronchopulmonary carcinoid; small intestine; chemotherapy; drug
sensitivity)
_________________________________________________________________________________________________
Received 2/25/08; Revised 4/20/08; Accepted
4/22/08.
1.
Correspondence:
Dr. Mark Kidd, Gastrointestinal Pathobiology Research Group, Yale
University School of Medicine, 333 Cedar Street, P. O. Box 208062, New
Haven, Connecticut 06520-8062, USA. Phone: 1-203-7855429. Fax:
1-203-7374067.
E-mail: mark.kidd@yale.edu
2.
Abbreviations:
NET,
neuroendocrine tumor; Topo, topoisomerase; mTOR,
mammalian
target of rapamycin.
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