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Inhibitory Effect of the Noncamptothecin Topoisomerase I Inhibitor LMP-400 on Female Mice Models and Human Pheochromocytoma Cells

Authors :
Schovanek, Jan
Bullova, Petra
Tayem, Yasin
Giubellino, Alessio
Wesley, Robert
Lendvai, Nikoletta
Nölting, Svenja
Kopacek, Juraj
Frysak, Zdenek
Pommier, Yves
Kummar, Shivaani
Pacak, Karel
Source :
Endocrinology; November 2015, Vol. 156 Issue: 11 p4094-4104, 11p
Publication Year :
2015

Abstract

Metastatic pheochromocytoma continues to be an incurable disease, and treatment with conventional cytotoxic chemotherapy offers limited efficacy. In the present study, we evaluated a novel topoisomerase I inhibitor, LMP-400, as a potential treatment for this devastating disease. We found a high expression of topoisomerase I in human metastatic pheochromocytoma, providing a basis for the evaluation of a topoisomerase 1 inhibitor as a therapeutic strategy. LMP-400 inhibited the cell growth of established mouse pheochromocytoma cell lines and primary human tumor tissue cultures. In a study performed in athymic female mice, LMP-400 demonstrated a significant inhibitory effect on tumor growth with two drug administration regimens. Furthermore, low doses of LMP-400 decreased the protein levels of hypoxia-inducible factor 1 (HIF-1α), one of a family of factors studied as potential metastatic drivers in these tumors. The HIF-1α decrease resulted in changes in the mRNA levels of HIF-1 transcriptional targets. In vitro, LMP-400 showed an increase in the growth-inhibitory effects in combination with other chemotherapeutic drugs that are currently used for the treatment of pheochromocytoma. We conclude that LMP-400 has promising antitumor activity in preclinical models of metastatic pheochromocytoma and its use should be considered in future clinical trials.

Details

Language :
English
ISSN :
00137227 and 19457170
Volume :
156
Issue :
11
Database :
Supplemental Index
Journal :
Endocrinology
Publication Type :
Periodical
Accession number :
ejs37146250
Full Text :
https://doi.org/10.1210/en.2015-1476