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

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.

journal_name

Endocrinology

journal_title

Endocrinology

authors

Schovanek J,Bullova P,Tayem Y,Giubellino A,Wesley R,Lendvai N,Nölting S,Kopacek J,Frysak Z,Pommier Y,Kummar S,Pacak K

doi

10.1210/en.2015-1476

subject

Has Abstract

pub_date

2015-11-01 00:00:00

pages

4094-104

issue

11

eissn

0013-7227

issn

1945-7170

journal_volume

156

pub_type

杂志文章

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