Specific Colon Cancer Cell Cytotoxicity Induced by Bacteriophage E Gene Expression under Transcriptional Control of Carcinoembryonic Antigen Promoter.

Ana Rama,Miguel Burgos,Consolación Melguizo,Gloria Perazzoli,Rosa Hernandez,Celia Vélez,Jose Prados

doi:10.3390/ijms160612601

Abstract

Colorectal cancer is one of the most prevalent cancers in the world. Patients in advanced stages often develop metastases that require chemotherapy and usually show a poor response, have a low survival rate and develop considerable toxicity with adverse symptoms. Gene therapy may act as an adjuvant therapy in attempts to destroy the tumor without affecting normal host tissue. The bacteriophage E gene has demonstrated significant antitumor activity in several cancers, but without any tumor-specific activity. The use of tumor-specific promoters may help to direct the expression of therapeutic genes so they act against specific cancer cells. We used the carcinoembryonic antigen promoter (CEA) to direct E gene expression (pCEA-E) towards colon cancer cells. pCEA-E induced a high cell growth inhibition of human HTC-116 colon adenocarcinoma and mouse MC-38 colon cancer cells in comparison to normal human CCD18co colon cells, which have practically undetectable levels of CEA. In addition, in vivo analyses of mice bearing tumors induced using MC-38 cells showed a significant decrease in tumor volume after pCEA-E treatment and a low level of Ki-67 in relation to untreated tumors. These results suggest that the CEA promoter is an excellent candidate for directing E gene expression specifically toward colon cancer cells.

Highlights

Colon cancer, along with breast and lung cancer, is one of the most prevalent cancers in the world [1].While in early stages, colon cancer is characterized by a good prognosis, in more advanced, metastatic stages, the five-year survival rate is only 10%
HTC-116 showed the highest level of luciferase among all of the colorectal cancer cells, while T-84 cells presented the least expression of cancer cells
Our study described the use of the carcinoembryonic antigen promoter (CEA) promoter to increase the colon cancer cell specificity of E gene expression and the subsequent tumor growth inhibition induced by expressing this cytotoxic gene

Summary

Introduction

Along with breast and lung cancer, is one of the most prevalent cancers in the world [1].While in early stages, colon cancer is characterized by a good prognosis, in more advanced, metastatic stages, the five-year survival rate is only 10%. Along with breast and lung cancer, is one of the most prevalent cancers in the world [1]. 25% of all colon cancer patients reach this stage and are principally treated with 5-fluorouracil (5-FU) alone or a combination of oxaliplatin (FOLFOX, a combo of oxaliplatin, 5-FU and leucovorin), irinotecan (FOLFIRI, a combo of irinotecan, 5-FU and leucovorin), angiogenesis inhibitors and/or epidermal growth factor receptor inhibitors [2]. Recent studies have investigated several aspects of gene therapy related to cancer treatment; one of these approaches is suicide gene therapy [3], which may enhance the potential of the drugs typically used to treat cancer [4], including colon cancer [5,6]

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