Co-Administration of Vadimezan and Recombinant Coagulase-NGR Inhibits Growth of Melanoma Tumor in Mice.

Amir Daei Farshchi Adli,Ramezan Behzadi,Khaled Seidi,Nosratollah Zarghami,Rana Jahanban-Esfahlan,Davoud Farajzadeh

doi:10.34172/apb.2021.037

Abstract

Purpose: Tumor vascular targeting appeared as an appealing approach to fight cancer, though, the results from the clinical trials and drugs in the market were proved otherwise. The promise of anti-angiogenic therapy as the leading tumor vascular targeting strategy was negatively affected with the discovery that tumor vascularization can occur non-angiogenic mechanisms such as co-option. An additional strategy is induction of tumor vascular infarction and ischemia.Methods: Such that we used truncated coagulase (tCoa) coupled to tumor endothelial targeting moieties to produce tCoa-NGR fusion proteins. We showed that tCoa-NGR can bypass coagulation cascade to induce selective vascular thrombosis and infarction of mild and highly proliferative solid tumors in mice. Moreover, combination therapy can be used to improve the potential of cancer vascular targeting modalities. Herein, we report combination of tCoa-NGR with vascular disrupting agent (VDA), vadimezan.Results: Our results show that synergistic work of these two agents can significantly suppress growth of B16-F10 melanoma tumors in C57/BL6 mice.Conclusion: For the first time, we used the simultaneous benefits of two strategies for inducing thrombosis and destruction of tumor vasculature as spatial co-operation. The tCoa-NGR induce thrombosis which reduces blood flow in the peripheral tumor region. And combined with the action of DMXAA, which target inner tumor mass, growth and proliferation of melanoma tumors can be significantly suppressed.

Highlights

The idea for targeting the tumor vascular system emerged as an interesting approach to treat cancer, the results from the clinical trials and drugs in the market were not much encouraging as it was expected.[1]
We showed that truncated coagulase (tCoa)-NGR can bypass coagulation cascade to induce selective vascular thrombosis and infarction of mild and highly proliferative solid tumors in mice
Co-administration of tCoa-NGR fusion proteins and DMXAA reduces tumor growth in mice Combined therapeutic effects of tCoa-NGR and DMXAA were evaluated in C57BL/6 mice bearing melanoma cancer

Summary

Introduction

The idea for targeting the tumor vascular system emerged as an interesting approach to treat cancer, the results from the clinical trials and drugs in the market were not much encouraging as it was expected.[1] This is, the promise of anti-angiogenic therapy as the popular and well-practiced vascular targeting approach in the clinic was soon hindered by the development of drug resistance, disease relapse, and metastasis, knowing that tumors can apply redundant angiogenic signaling pathways.

Objectives

Methods

Results