• Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
HYPOTHESIS
Year : 2017  |  Volume : 3  |  Issue : 3  |  Page : 106-108

Possibility of specific expression of the protein toxins at the tumor site with tumor-specialized promoter


1 Department of Otolaryngology, Head and Neck Surgery, No. 1 Hospital of Shanxi Medical University, Taiyuan, Shanxi; Department of Otolaryngology, Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, Taiyuan, Shanxi, China
2 Department of Neurosurgery, Shanxi Provincial People's Hospital, Taiyuan, Shanxi, China

Date of Submission13-Oct-2016
Date of Acceptance21-Feb-2017
Date of Web Publication8-Jun-2017

Correspondence Address:
Binquan Wang
Department of Otolaryngology, Head and Neck Surgery, No. 1 Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi
China
Changchen Hu
Department of Neurosurgery, Shanxi Provincial People's Hospital, Taiyuan 030012, Shanxi
China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ctm.ctm_50_16

Rights and Permissions
  Abstract 

The ultimate goal of cancer therapy is to establish a treatment regimen that will ensure complete eradication of cancers with minimal toxicity to the surrounding normal tissues. Protein toxins are highly efficient when they are used as treatment reagents of cancer but are associated with toxicity in normal tissues. Given that specialized promoters have been widely investigated for specific expressions, we speculated that tumor-specialized promoters would play an important role in protein toxin tumor therapy. Therefore, we hypothesize that a tumor-specialized promoter can be inserted into a truncated protein toxin expression vector. Then, the vector can be introduced into the human body by either a viral or nonviral vector. These protein toxin genes would be specifically expressed in tumor cells, but not in normal tissue cells. The proposition may provide a new strategy with the development of protein toxins for specific targeting to neoplastic tumors.

Keywords: Gene therapy, protein toxins, tumor-specialized promoter


How to cite this article:
Zhou L, Li Y, Hu C, Wang B. Possibility of specific expression of the protein toxins at the tumor site with tumor-specialized promoter. Cancer Transl Med 2017;3:106-8

How to cite this URL:
Zhou L, Li Y, Hu C, Wang B. Possibility of specific expression of the protein toxins at the tumor site with tumor-specialized promoter. Cancer Transl Med [serial online] 2017 [cited 2019 May 25];3:106-8. Available from: http://www.cancertm.com/text.asp?2017/3/3/106/203892


  Introduction Top


Over the past several years, protein toxins have attracted enormous interest as targeted therapeutics.[1] Protein toxins were truncated to delete their binding domain, allowing for selective ligand-directed binding. Monoclonal antibodies and growth factor fusion toxins are often considered immunotoxins.[2] A number of such protein toxin reagents are in clinical use. The most potent immunotoxins are made from bacterial and plant toxins. Plant toxins, particularly ricin, are useful for chemically conjugating to monoclonal antibodies and have shown clinical activity in several types of lymphoma and leukemia. Their dose is generally limited by vascular leak syndrome.[3] Bacterial toxins, particularly pseudomonas exotoxin (PE) and diphtheria toxin, have been used to produce single-chain fusions with either growth factors or recombinant antibody fragments.[4] The immunotoxin binds to a surface antigen on a cancer cell, enters the cell by endocytosis, and kills it.


  Problem of the Protein Toxins Targeted to Solid Tumor Top


Theoretically, recombinant immunotoxins can selectively kill target antigen-positive cancer cells but are associated with unspecific toxicity in normal tissues that contain the same target antigen. This is not a problem if the immunotoxins are used to target antigens on B- or T-cell malignancies as normal B- and T-cells can be regenerated from antigen-negative stem cells.[5] However, it is a serious problem if solid tumors are targeted as the antigen can be present in vital organs, and thus the immunotoxin will kill normal cells in such tissues.[6] It is essential that targeted inhibition is restricted to tumors, and that nontargeted normal cells are free from such inhibitions. In addition, direct delivery of an immunotoxin-fused protein in a fully immunocompetent setting is problematic because of antibody neutralization and inability to localize tumor cells.[7]

The success of targeted gene therapy for cancer depends on the specific delivery of genes to targeted cells,[8] similar to immunotoxin-targeted therapy which also depends on a successful delivery system. To reduce unspecific toxicity in normal tissues, several attempts have been made where genetically engineered adult somatic cells, such as lymphokine-activated killer cells [9] and antigen-specific T-cells,[10],[11] served as a platform for the delivery of immunotoxin genes to tumors. Facilitated by leader sequences, these cells were capable of targeting tumors and releasing immunotoxins at the tumor site. In these studies, although tumor growth was disturbed (or affected) by the immunotoxins secreted by these cells, tumor was only slowly growing and did not provide a cure. Moreover, the preparation of different tumor antigen-specific T-cells is tedious and difficult. In addition, it remains to be determined whether it would be necessary to stimulate T-cells with antigen before administration, or whether the cancer cells within the patient might provide enough antigen stimulation.[12]

Although these toxins (in vivo or ex vivo) have been widely investigated in gene therapy, tumor-specialized promoters have not been previously used for toxin expression to reduce toxicity in normal tissues. Thus, we suggest a novel toxin expression system for targeting tumors, given tumor-specialized promoter controls. This would allow for the specific expression of the toxins only at the tumor site.


  Hypothesis Top


According to the above research, we bring forward a new method of toxin expression at the tumor site based on tumor-specialized promoter controls: these protein toxin genes are truncated to delete their binding domain and keep their translocation and catalytic domains. An entire expression cassette (including specialized promoters and termination signals) is inserted into the protein toxin expression vector. Then, the complete protein toxin gene containing specialized promoters is introduced into the human body through viral vector or nonviral vector. These protein toxin genes would be specifically expressed in the tumor cells, but not in the normal tissue cells. Thus, this minimally toxic treatment regimen would be more thorough in cancer treatment depending on the toxicity to eukaryotic cells.

Protein toxins are capable of killing a cell when a single molecule reaches the cytosol. They are highly efficient when they serve as treatment reagents of cancer but are associated with toxicity in normal tissues. Complete protein toxins, such as PE, have three functional domains. Domain I is located at the N-terminus. It is the cell-binding domain. Domain II has translocation activity. Domain III is located at the C-terminus. It catalyzes the adenosine diphosphate-ribosylation and inactivation of elongation factor 2, which leads to the inhibition of protein synthesis and cell death.[13] PE38 is a truncated form of PE which has been used in the construction of fusion toxins and is an ideal candidate for cancer gene therapy.[9],[10]

The ultimate goal of cancer therapy is to provide a minimally toxic treatment regimen that will ensure complete eradication of cancers. Since protein toxins have essential qualities as potential gene therapies for cancer, many studies focus on studying targeted cell-binding moiety of immunotoxin treatment.[14] Despite the progress of the bioinformatics approach to characterize cell surface antigens and receptors on tumor cells, it remains difficult to generate novel cancer-specific monoclonal antibody or growth factors.[15],[16],[17] There is small amount of research on specialized promoters of protein toxins for specific targeting to neoplastic tumors.

In our hypothesis, we engineered cancer cell-specific expression vectors, in which the expression of protein toxins is driven by a tumor cell's specialized promoter, which functions selectively in various cancer cells with no activity in normal cells. Tumor cell-specialized promoters were cloned as an upregulated transcript from human cancer cells of diverse origins. It will be inspiring that the ideal tumor cell-specialized promoters drive transgene expression in universal cancers.


  Conclusion Top


We believe that a targeting toxin expression system with tumor-specialized promoter is a promising modality for gene therapy. By activating specific signals in cancer cells, tumor-specialized promoters drive local specific expression of the toxins only at the tumor site. We may achieve a course of treatment that promotes the destruction of tumor cells, with little or no effect on normal cells. This represents the main objective of cancer gene therapy.


  Acknowledgment Top


We thank Prof. Pastan Ira (NCI, NIH) for his kind gift of plasmid-containing PE and Dr. David Cushley for critical reading of the manuscript.

Financial support and sponsorship

This research was supported by the National Science Foundation of China (No. 30901774) and the Shanxi Province Science Foundation (No. 2014011038-2).

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Johannes L, Decaudin D. Protein toxins: intracellular trafficking for targeted therapy. Gene Ther 2005; 12 (18): 1360–8.  Back to cited text no. 1
    
2.
Pastan I. Targeted therapy of cancer with recombinant immunotoxins. Biochim Biophys Acta 1997; 1333 (2): C1–6.  Back to cited text no. 2
    
3.
Sandvig K, van Deurs B. Entry of ricin and Shiga toxin into cells: molecular mechanisms and medical perspectives. EMBO J 2000; 19 (22): 5943–50.  Back to cited text no. 3
    
4.
Boquet P. Bacterial toxins inhibiting or activating small GTP-binding proteins. Ann N Y Acad Sci 1999; 886: 83–90.  Back to cited text no. 4
[PUBMED]    
5.
Batlevi CL, Matsuki E, Brentjens RJ, Younes A. Novel immunotherapies in lymphoid malignancies. Nat Rev Clin Oncol 2016; 13 (1): 25–40.  Back to cited text no. 5
    
6.
Pai-Scherf LH, Villa J, Pearson D, Watson T, Liu E, Willingham MC, Pastan I. Hepatotoxicity in cancer patients receiving erb-38, a recombinant immunotoxin that targets the erbB2 receptor. Clin Cancer Res 1999; 5 (9): 2311–5.  Back to cited text no. 6
    
7.
Pastan I, Hassan R, FitzGerald DJ, Kreitman RJ. Immunotoxin treatment of cancer. Annu Rev Med 2007; 58: 221–37.  Back to cited text no. 7
[PUBMED]    
8.
Vile RG, Russell SJ, Lemoine NR. Cancer gene therapy: hard lessons and new courses. Gene Ther 2000; 7 (1): 2–8.  Back to cited text no. 8
    
9.
Chen SY, Yang AG, Chen JD, Kute T, King CR, Collier J, Cong Y, Yao C, Huang XF. Potent antitumour activity of a new class of tumour-specific killer cells. Nature 1997; 385 (6611): 78–80.  Back to cited text no. 9
    
10.
Vallera DA, Jin N, Baldrica JM, Panoskaltsis-Mortari A, Chen SY, Blazar BR. Retroviral immunotoxin gene therapy of acute myelogenous leukemia in mice using cytotoxic T cells transduced with an interleukin 4/diphtheria toxin gene. Cancer Res 2000; 60 (4): 976–84.  Back to cited text no. 10
    
11.
Zhang T, Cao L, Zhang Z, Yue D, Ping Y, Li H, Huang L, Zhang Y. Review of cancer immunotherapy: application of chimeric antigen receptor T cells and programmed death 1/programmed death-ligand 1 antibodies. Cancer Transl Med 2015; 1 (2): 43–9.  Back to cited text no. 11
    
12.
Kershaw MH, Teng MW, Smyth MJ, Darcy PK. Supernatural T cells: genetic modification of T cells for cancer therapy. Nat Rev Immunol 2005; 5 (12): 928–40.  Back to cited text no. 12
    
13.
FitzGerald DJ, Willingham MC, Pastan I. Pseudomonas exotoxin-immunotoxins. Cancer Treat Res 1988; 37: 161–73.  Back to cited text no. 13
[PUBMED]    
14.
Pastan I, Hassan R, Fitzgerald DJ, Kreitman RJ. Immunotoxin therapy of cancer. Nat Rev Cancer 2006; 6 (7): 559–65.   Back to cited text no. 14
    
15.
Kawakami K, Nakajima O, Morishita R, Nagai R. Targeted anticancer immunotoxins and cytotoxic agents with direct killing moieties. ScientificWorldJournal 2006; 6: 781–90.  Back to cited text no. 15
[PUBMED]    
16.
Li Q, Tu Y. Emerging concepts in glioma biology: implications for clinical protocols and rational treatment strategies. Cancer Transl Med 2015; 1 (5): 176–80.  Back to cited text no. 16
    
17.
Qi J, Yang H, Wang X, Tu Y. The progress in molecular biomarkers of gliomas. Cancer Transl Med 2016; 2 (4): 125–9.  Back to cited text no. 17
    




 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Problem of the P...
Hypothesis
Conclusion
Acknowledgment
References

 Article Access Statistics
    Viewed1204    
    Printed32    
    Emailed0    
    PDF Downloaded93    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]