Application of Microbial Toxins for Cancer Therapy
01 Jan 2012-pp 647-662
TL;DR: Continuous efforts are being made to improve the specificity and efficacy of immunotoxins, to reduce size effects of the drugs, reduce immunogenicity and to improve better pharmacokinetics for drugs delivery.
Abstract: The principle of selective targeting of immunotoxins lies on the basis that cancer cells usually have few or specific growth factors/receptors/antigens highly over expressed on their surface. Ligands corresponding to these molecules are conjugated to modified toxins (modified to loss its native function) isolated form variety of bacterial populations. Normal cells either do not express these molecules or express at relatively low number leading to no or minimal adverse effects. The basic mechanism of action of these immunotoxins depends on the toxins employed. In this regard continuous efforts are being made to (i) Identity molecules exclusively expressed in cancer cells, (ii) to improve the specificity and efficacy (iii) reduce size effects of the drugs, (iv) Reduce immunogenicity and (v) to improve better pharmacokinetics for drugs delivery.
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TL;DR: Assessment of the immunoreactivity of a SEB-coding DNA construct that serves as a DNA vaccine for breast cancer therapy revealed that apparently the construct could be efficiently expressed in mouse model, and could act as an amenable adjuvant in cancer immunotherapy.
Abstract: Immunotherapy has been suggested as a compelling alternative approach for conventional breast cancer treatment methods. Despite the paramount rolesof T cells in this approach, insufficient numbers of them in the combat against progressive tumor growth still remain to be dealt with. Super antigens are a class of antigens, capable of eliciting T cell proliferation response against desired antigens. Staphylococcal enterotoxin B (SEB) is categorized as a super antigen, its anti-tumor properties has been previously reported. However, to the best our knowledge, SEB has not been ever administered as a DNA construct. In the present study, we exploited bioinformatics tools to assess the immunoreactivity of a SEB-coding DNA construct that serves as a DNA vaccine for breast cancer therapy. Potential B and T (MHC class I and II binders) cell epitopes of the hypothetically expressed protein, along with its sub cellular localization were predicted. Moreover, probable glycosylation and phosphorylation sites within the protein sequence were determined. The gene sequence was optimized according to murine model codon bias and its mRNA stability was analyzed. Employing an integrative in silico approach, we revealed that apparently the construct could be efficiently expressed in mouse model. Moreover, the hypothetically expressed protein could act as an amenable adjuvant in cancer immunotherapy.
21 citations
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TL;DR: The crystal structure of the diphtheria toxin dimer at 2.5 Å resolution reveals a Y-shaped molecule of three domains that can be useful in designing chimaeric proteins, such as immunotoxins, in which the receptor-binding domain is substituted with antibodies to target other cell types.
Abstract: The crystal structure of the diphtheria toxin dimer at 2.5 A resolution reveals a Y-shaped molecule of three domains. The catalytic domain, called fragment A, is of the alpha + beta type. Fragment B actually consists of two domains. The transmembrane domain consists of nine alpha-helices, two pairs of which are unusually apolar and may participate in pH-triggered membrane insertion and translocation. The receptor-binding domain is a flattened beta-barrel with a jelly-roll-like topology. Three distinct functions of the toxin, each carried out by a separate structural domain, can be useful in designing chimaeric proteins, such as immunotoxins, in which the receptor-binding domain is substituted with antibodies to target other cell types.
651 citations
TL;DR: Charting the Th response against human melanoma as well as other tumors is important for the development of optimal anticancer vaccines and for the design of other T cell–related therapeutic modalities in cancer.
Abstract: The specificity and power of the cellular arm of the immune system may provide new therapeutic approaches to cancer. With the assumption that T cells might be able to recognize and eliminate cancer cells with the same efficiency as virus-infected cells, investigators have searched many years for ways to trigger or amplify the patient's inadequate immune response to tumors. Much attention has been given to the role of CD8+ CTLs because most tumors are MHC class I positive, but negative for MHC class II. Moreover, CD8+ CTLs are able to lyse tumor cells directly upon recognition of peptide–MHC class I complexes expressed by the tumor, and their ability to eradicate large tumor masses in vivo has been demonstrated. The focus in cancer immunology on CD8+ T cell responses is also exemplified by an increasing list of tumor antigens identified by tumor-reactive CD8+ CTLs. CD4+ Th cells have received far less attention, which is remarkable given the pivotal role of these cells in regulating most antigen-specific immune responses. Until now, only a few Th epitopes derived from human tumor antigens recognized by CD4+ Th cells have been identified (1, 2). Three studies published in this issue describe the identification of melanoma antigens that are recognized by CD4+ T cells in the context of MHC class II molecules (3–5). Charting the Th response against human melanoma as well as other tumors is important for the development of optimal anticancer vaccines and for the design of other T cell–related therapeutic modalities in cancer.
541 citations
Journal Article•
TL;DR: A far more detailed knowledge of surface antigens of tumor cells will be necessary before the possibility of immunological control of cancer is assessed, and biochemical and genetic characterization of Class 1 antIGens represents an essential next step in evaluating the significance of theseAntigens.
Abstract: The major focus of cancer immunology has shifted away from arguments about the validity of the immunosurveillance theory of cancer to the more basic question of tumor-specific antigens. Despite vast effort aimed at demonstrating such antigens, their existence in the generality of cancer remains unproven. Serological analysis of three tumor types, mouse leukemia, mouse sarcoma, and human malignant melanoma, has received most attention, and a rudimentary classification of the surface antigens expressed by these tumors has begun to emerge. The prime candidates for antigens that can be considered tumor specific are the few instances of Class 1 antigens that have now been serologically defined on mouse and human tumors. These antigens show an absolute restriction to individual tumors, not being demonstrable on any other normal or malignant cell type. Biochemical and genetic characterization of Class 1 antigens represents an essential next step in evaluating the significance of these antigens. The surprising features of the Thymus Leukemia (TL) antigens of the mouse provide insight into the genetic origin of another key class of tumor antigens, in this case antigens with characteristic properties of both differentiation antigens and tumor-specific antigens. In normal mice, TL antigens are restricted to cells in the thymus, and strains differ with regard to expression versus nonexpression of TL antigens. Genetic information for TL is universal in the mouse, however, as leukemias developing in mice that normally lack TL are found to express TL. What is clear from the past two decades of research in cancer immunology is that a far more detailed knowledge of surface antigens of tumor cells will be necessary before we can begin to assess the possibility of immunological control of cancer.
396 citations
TL;DR: This work shows that the B45 fragment forms, in lipid bilayers, pores that are large enough (diameter greater than or equal to 18 A) to allow the passage of extended fragment A into the cytosol of sensitive cells.
Abstract: The cytotoxic effect of diphtheria toxin requires the entry of its enzymatic A fragment (Mr approximately 21,000) into the cytosol of sensitive cells. We show that the B45 fragment (Mr approximately 24,000) forms, in lipid bilayers, pores that are large enough (diameter greater than or equal to 18 A) to allow the passage of extended fragment A. Pore formation is maximal when the B45-containing side is at low pH (4.7) and the opposite side is at high pH (7.4). These conditions resemble the pH gradient existing across lysosomal membranes. We suggest that fragment A passes through these pores from acidic endocytotic vesicles (lysosomes?) to the cytosol.
323 citations
TL;DR: The TNM process, which was introduced in 2002, will be tested over the next 3–4 years and evaluated and increased involvement by the experts should improve the understanding and dissemination of the TNM classification.
Abstract: The TNM classification is a worldwide benchmark for reporting the extent of malignant disease and is a major prognostic factor in predicting the outcome of patients with cancer. The objectives for cancer staging were defined by the International Union Against Cancer (UICC) TNM Committee almost 50 years ago and are still broadly applicable today. To keep pace with the modern demands of evidence-based practice, the UICC introduced a structured process for introducing changes to the TNM classification. The elements of the TNM process were determined to include the development of unambiguous criteria for the information and documentation required to consider changes in the classification, establishment of a well-defined process for the annual review of relevant literature, formation of site-specific expert panels, and the participation of experts from all over the world in the TNM review process. Communication between the oncology community and those involved in the TNM classification was established as being essential to the success of the process. The process, which was introduced in 2002, will be tested over the next 3-4 years and evaluated. In addition to the formal process, individual initiative, involvement by the national staging committees, and group consensus are required. Furthermore, increased involvement by the experts should improve the understanding and dissemination of the TNM classification.
237 citations