In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 25, No. 18_suppl ( 2007-06-20), p. 15041-15041
Abstract:
15041 Background: MIT, also known as aureolic acid and plicamycin (Mithracin), is an aureolic acid-type polyketide produced by various soil bacteria of the genus Streptomyces. Previous studies have shown that MIT exhibits antitumor activity. In the present study, we examine the antiangiogenic effect of MIT and its underlying mechanisms. Methods: Cohorts of 10 athymic BALB/c nude mice were implanted with 1.5 million human H727 carcinoid cells. Mice were treated with subcutaneous or intraperitoneal 0.2 mg/kg of mithramycin twice weekly once implanted tumor reached 4 mm in size. Results: Both subcutaneous and intraperitoneal MIT significantly suppressed the growth of carcinoid cells in nude mouse models (median tumor weight in PBS, s.c., i.p. groups 790 mm 3 vs 280 mm 3 , 480 mm 3 ; P 〈 0.01). We also evaluated the Sp1 expression in growing tumors and various organs. We found that the liver expressed the highest level of Sp1 among normal organs (including liver, stomach, large intestine, and small intestine, spleen, kidney, brain and lymph node). However, Sp1 expression in the growing tumors was more than 10 times higher than that in a normal liver. Treatment with MIT reduced the Sp1 expression in the tumors, while no discernible effect on Sp1 expression in normal tissues was observed. This is the first demonstration that MIT selectively inhibited the Sp1 expression in the growing tumors. Consistent with the expression of Sp1, a substantial suppression of VEGF, PDGF, EGFR, and IGFR expression was evident. Finally, treatment with MIT reduced the microvessel formation in tumors by 80% (MVD count; P 〈 0.01). This antiangiogenic activity was confirmed by in vitro tubulogenesis assay and in vivo Matrigel plug assay. Conclusions: Collectively, our studies strongly indicate that MIT is a potent antiangiogenic agent and its mechanism of action involved suppression of Sp1 expression and its consequent downregulation of its downstream targets including VEGF, PDGF, EGFR, and IGFR that are key to tumor angiogenesis. No significant financial relationships to disclose.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2007.25.18_suppl.15041
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2007
detail.hit.zdb_id:
2005181-5
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