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Potent and sustained inhibition of HIF-1α and downstream genes by a polyethyleneglycol-SN38 conjugate, EZN-2208, results in anti-angiogenic effects
- Source :
- Angiogenesis
- Publication Year :
- 2011
- Publisher :
- Springer Netherlands, 2011.
-
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. Electronic supplementary material The online version of this article (doi:10.1007/s10456-011-9209-1) contains supplementary material, which is available to authorized users.
- Subjects :
- Cancer Research
MMP2
Physiology
Angiogenesis
Clinical Biochemistry
HIF-1α
Down-Regulation
Mice, Nude
Angiogenesis Inhibitors
Pharmacology
Biology
Irinotecan
Polyethylene Glycols
Mice
Western blot
Glioma
Cell Line, Tumor
medicine
Animals
Humans
Matrigel
Original Paper
medicine.diagnostic_test
Neovascularization, Pathologic
Pegylation
medicine.disease
Hypoxia-Inducible Factor 1, alpha Subunit
Antineoplastic Agents, Phytogenic
Xenograft Model Antitumor Assays
Neoplasm Proteins
Gene Expression Regulation, Neoplastic
Chorioallantoic membrane
SN38
CPT-11 (Camptosar)
Cell culture
Camptothecin
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 15737209 and 09696970
- Volume :
- 14
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Angiogenesis
- Accession number :
- edsair.doi.dedup.....987e4b070750cb0875c175fc4957ccf4