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.

• MeSH
• Benzodioxoles administration & dosage   pharmacology   MeSH
• PC12 Cells MeSH
• DNA Topoisomerases, Type I metabolism   MeSH
• Hypoxia-Inducible Factor 1, alpha Subunit genetics   metabolism   MeSH
• Pheochromocytoma drug therapy   enzymology   pathology   MeSH
• Cell Hypoxia MeSH
• Topoisomerase I Inhibitors administration & dosage   pharmacology   MeSH
• Isoquinolines administration & dosage   pharmacology   MeSH
• Rats MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Mice, Nude MeSH
• Cell Line, Tumor MeSH
• Tumor Cells, Cultured MeSH
• Liver Neoplasms drug therapy   enzymology   secondary   MeSH
• Adrenal Gland Neoplasms drug therapy   enzymology   pathology   MeSH
• Lung Neoplasms drug therapy   enzymology   secondary   MeSH
• Reverse Transcriptase Polymerase Chain Reaction MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents pharmacology   MeSH
• Gene Expression Regulation, Neoplastic drug effects   MeSH
• Drug Synergism MeSH
• Dose-Response Relationship, Drug MeSH
• Blotting, Western MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, N.I.H., Intramural MeSH
• Names of Substances
• Benzodioxoles MeSH
• DNA Topoisomerases, Type I MeSH
• Hypoxia-Inducible Factor 1, alpha Subunit MeSH
• HIF1A protein, human MeSH Browser
• Topoisomerase I Inhibitors MeSH
• Isoquinolines MeSH
• NSC 724998 MeSH Browser
• Antineoplastic Agents MeSH