Canstatin gene electrotransfer combined with radiotherapy: preclinical trials for cancer treatment

Abstract

Given as a prophylactic treatment, a single muscle electrogene transfer of plasmid coding canstatin fused to human serum albumin (CanHSA), slowed down the development of two xenografted human carcinomas from mammary (MDA-MB-231) and prostate origin (PC-3) in nude mice and delayed lung metastatic spreading of B16F10 melanoma cells in syngenic mice. No effect was observed with unfused canstatin. The long lasting circulating blood level of CanHSA (20 ng ml À1 ) resulted in a profound disorganization of the tumor blood vessel network. However, when used as a curative treatment, on well-established tumors, CanHSA electrogenetherapy was ineffective in reducing tumor growth.As radiation is known to increase the avb3 and avb5 integrins, which are canstatin receptors, to extend the use of CanHSA electrogenetherapy, as a curative treatment, we explored the combination of CanHSA and ionizing radiation. We demonstrated a better efficacy (P ¼ 0.01) of the bitherapy over irradiation alone, as a result of strong vessel disorganization and dramatic increase of tumor cells apoptosis. This extremely simple virus free curative protocol could open the door to potential clinical applications, especially for prostate cancer that often develops radioresistance.

Antitumorigenic effects of a mutant of the heparin affin regulatory peptide on the U87 MG glioblastoma cell line

“…After xylene treatment and rehydration, hematoxylin/eosin/safranin‐stained slides were prepared. Immunohistochemistry was carried out as previously described 23. Immunohistochemistry of CD34 and HARP was carried out as described previously 16.…”

Mitochondria as targets in angiogenesis inhibition

“…Future clinical application is thus dependent on the development of agents that could raise the level of endogenous expression, or enhance their mobilisation from the ECM. Gene therapy seems to have answered this need to some extent (Folkman, 2006b;Magnon et al, 2008). The Folkman laboratory are currently developing modified forms of Endostatin to allow up scaled production of the protein, whilst a variant of the protein named Endostar (Medgenn Bioengineering Yantai, China), has recently been approved by the FDA China for non-small cell cancer of the lung (Ling et al, 2007).…”

Endogenous Matrix-Derived Inhibitors of Angiogenesis

“…It also delays the metastatic process, as observed in mice with B16F10 melanomas [113]. Both the N-terminal and C-terminal part of canstatin exhibits anti-tumor activity in B16 murine melanomas [104,105], but the reason for tumor response in vivo was not assessed in these experiments.…”

“…Whereas radiation alone upregulates HIF1 signaling to promote radioresistance, the addition of canstatin interacts with HIF1 signaling and causes apoptosis [112]. In another study the upregulation of integrin αvβ3 and αvβ5 caused by radiotherapy sensitizes various malignant tumors in mice to canstatin, facilitating disorganization of the tumor vasculature and extensive tumor cell apoptosis [113]. Canstatin has also been shown to increase the anti-tumor effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene therapy [114].…”