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Book ChapterDOI

Application of Microbial Toxins for Cancer Therapy

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.
Citations
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Journal ArticleDOI
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

References
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Journal ArticleDOI
TL;DR: The mutant has the capacity to form a transmembrane structure similar to that of the wild-type T domain and, thus, that introduction of charged groups in membrane-penetrating regions of a protein does not introduce an insurmountable barrier to trans Membrane movement.
Abstract: The low pH triggered membrane insertion of the T domain of diphtheria toxin is a critical step in the translocation of the C domain of the toxin across membranes in vivo. We previously established ...

49 citations

Journal ArticleDOI
TL;DR: Limited evidence indicates that blood NK levels need not be representative of the activity of tumor associated lymphoid cells, although suppression of the in vitro maintenance of cytotoxicity by in situ macrophages and lymphocytes has been described in a few patients.
Abstract: Natural killer (NK) cells have been studied in human neoplastic diseases in an effort to assess the role of these cells in the control of human neoplasia and to monitor the effects of therapeutic regimens expected to affect this reactivity. NK activity measured against susceptible cell lines is usually somewhat depressed in patients bearing advanced solid tumors, but not at early disease stages. Lymphoid cells associated with solid tumor tissues or effusions have usually low NK cytotoxicity, with considerable differences among histologic types (e.g., nasopharyngeal carcinoma versus other tumors) or at different sites involved by the same tumor (e.g., peritoneal effusions versus solid lesions in ovarian carcinoma). The low levels of NK activity of tumor-associated lymphoid cells are primarily related to a low frequency in the relevant effector cells at the tumor site, although suppression of the in vitro maintenance of cytotoxicity by in situ macrophages and lymphocytes has been described in a few patients. Treatment with immunopharmacologic agents, interferons in particular, has been reported to augment NK activity in cancer patients, but it is unclear how blood NK activity relates to tissue levels of this reactivity. Limited evidence indicates that blood NK levels need not be representative of the activity of tumor associated lymphoid cells. Most studies on NK cells in human neoplasia have dealt with reactivity against susceptible tissue culture lines, but freshly isolated human tumors are generally relatively resistant to these effector cells, particularly when autologous lymphoid cells are used. The resistance of fresh human neoplastic cells to NK activity has not been studied extensively and, together with the poor localization at the tumor site of NK effectors, it represents a major difficulty in envisaging a role for these cells in the control of established human neoplasia.

48 citations

Journal ArticleDOI
TL;DR: Based on the presence of high affinity interleukin-2 receptor (IL-2R) on CLL cells, therapy of relapsed CLL patients with a diphtheria fusion protein targeting IL-2r was tested in a pilot Phase II study as mentioned in this paper.
Abstract: Despite multiple new therapeutic options for patients with chronic lymphocytic leukaemia (CLL), the prognosis of patients with relapsed disease is poor. After first-line therapy with fludarabine, alkylating agents, rituximab or combinations of these agents, most patients relapse within a few years. While second-line therapy with alemtuzumab, or other combinations of the above agents, have produced remissions, most of these are partial responses lasting months rather than years. Patients commonly die from progressive disease or infections related to the underlying disease or treatment. The authors sought to develop a novel therapeutic with the capacity to kill chemotherapy-resistant CLL cells and with reduced toxicities to normal tissues. Based on the presence of high affinity interleukin-2 receptor (IL-2R) on CLL cells, therapy of relapsed CLL patients with a diphtheria fusion protein targeting IL-2R - DAB(389)IL2 (ONTAK), Seragen, Inc., Hopkinton, MA, USA) - was tested in a pilot Phase II study. Biological activity and a partial remission were observed with modest drug-related side effects. Based on these encouraging findings, alternative schedules and combinations with agents that may enhance CLL cell expression of IL-2R are being tested. Hopefully, the use of these targeted therapeutic approaches will provide additional therapeutic options with fewer side effects for this common and incurable condition.

45 citations

Journal ArticleDOI
TL;DR: In vitro protein-DNA binding experiments are performed, establishing that a corynebacterial Fe2+-sensitive protein, named DtoxR, can bind to a palindromic motif present in the tox promoter region, providing evidence that DToxR is responsible for the repression of toxinogenesis observed in iron-containing growth medium.
Abstract: Previous studies provided indirect evidence that in Corynebacterium diphtheriae regulation of diphtheria toxin gene (tox) transcription by iron is mediated by a bacterial repressor. By performing in vitro protein-DNA binding experiments, we establish that a corynebacterial Fe2+-sensitive protein, named DtoxR, can bind to a palindromic motif present in the tox promoter region. Binding of this factor prevents the interaction of the transcription initiation machinery with presumptive critical promoter elements, providing evidence that DtoxR is responsible for the repression of toxinogenesis observed in iron-containing growth medium.

44 citations

Journal ArticleDOI
TL;DR: The results suggest that the effects of physiologically achievable concentrations of butyrate on IL-2R expression could be exploited to enhance the susceptibility of intermediate and low-affinity IL- 2R expressing leukemia cells to DAB(389)IL-2.

37 citations