Potent and sustained inhibition of HIF-1α and downstream genes by a polyethyleneglycol-SN38 conjugate, EZN-2208, results in anti-angiogenic effects.

Abstract

Topoisomerase I inhibitors down-regulate HIF-1α leading to tumor growth inhibition, but only while maintaining sustained levels of drug exposure. EZN-2208, a multi-arm 40 kDa pegylated, releasable SN38-drug conjugate, provides higher, longer lasting exposure of tumors to SN38 in contrast to SN38 that is released from CPT-11. EZN-2208 also consistently has greater antitumor activity than CPT-11 in a variety of solid and hematological tumor models. In this report, the ability of PEG-SN38 to down-regulate HIF-1α and its downstream targets, in a more potent, sustained manner compared with CPT-11 was examined. To do so, U251 glioma xenografts that stably expressed a hypoxia response element-dependent luciferase reporter gene were implanted in mice. After treatment it was found that EZN-2208 induced potent, sustained HIF-1α down-regulation (37% at 48 h and 83% at 120 h) in the tumors, whereas CPT-11 caused only minor, transient HIF-1α down-regulation. In addition, EZN-2208 down-regulated mRNA levels of HIF-1α targeted genes (MMP2, VEGF1, Glut1, Glut3 and TGFβ1). Further, western blot analyses of xenograft tumors demonstrated that EZN-2208 had significantly more effect than CPT-11 in down-regulating HIF-1α, VEGF, Glut1 and MMP2 protein levels. Significant down-regulation of HIF-1α and VEGF proteins translated to EZN-2208's superior anti-angiogenic activity compared with CPT-11, confirmed by microvessel density reduction in a chorioallantoic membrane assay and in CD-31 immunohistochemistry studies. Additional studies done with matrigel implants devoid of tumor cells show that EZN-2208 significantly inhibits angiogenesis while CPT-11 has little or no effect. It is concluded that the superior antitumor activity of EZN-2208 compared with CPT-11 is attributed, in part, to an anti-angiogenic effect. Ongoing clinical Phase I and Phase II studies will assess safety and efficacy of EZN-2208.

• Authors: Puja Sapra, Patricia Kraft, Fabio Pastorino, Domenico Ribatti, Melissa Dumble, Mary Mehlig, Maoliang Wang, Mirco Ponzoni, Lee M Greenberger, Ivan D Horak
• Journal: Angiogenesis (Angiogenesis) Vol. 14 Issue 3 Pg. 245-53 (Sep 2011) ISSN: 1573-7209 [Electronic] Germany
• PMID: 21452059 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents, Phytogenic
• EZN-2208
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Neoplasm Proteins
• Polyethylene Glycols
• Irinotecan
• Camptothecin

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Camptothecin (analogs & derivatives, pharmacology)
• Cell Line, Tumor
• Down-Regulation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Glioma (drug therapy, metabolism, pathology)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (biosynthesis)
• Irinotecan
• Mice
• Mice, Nude
• Neoplasm Proteins (biosynthesis)
• Neovascularization, Pathologic (drug therapy, metabolism, pathology)
• Polyethylene Glycols (pharmacology)
• Xenograft Model Antitumor Assays