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: DAB389IL2 at tolerable doses decreased tumor burden in each of these four standard treatment refractory CTCL patients and may offer an important alternative to standard palliative chemotherapy regimens.
Abstract: Four patients with late stage cutaneous T cell lymphoma (IB-IVA) who had failed at least two previous therapies were treated with DAB389IL2 at 9 or 18 microg/kg as 15-min intravenous infusions daily for 5 days every 3 weeks for eight cycles. Mild vascular leak syndrome (VLS) with transient edema, hypoalbuminemia, weight gain, and myalgias was observed in two of the patients lasting 7-10 days and only occurring on the first cycle. One stage IB patient had a pathologic complete remission (CR) lasting 11+ months from treatment initiation, one stage IIB patient had a complete clinical remission (CCR) lasting >6 months with complete clearing of a large tumor lasting >18 months, and one stage IIB and the one stage IVA patient had partial remissions (80-99% reduction in tumor masses) lasting 5 months. While IL2 receptor (IL2R) was expressed on 20-50% of tumor cells prior to therapy, recurrent tumor was IL2R negative in three of the patients. DAB389IL2 at tolerable doses decreased tumor burden in each of these four standard treatment refractory CTCL patients and may offer an important alternative to standard palliative chemotherapy regimens.
67 citations
Journal Article•
TL;DR: A wide range of growth factors has been identified in recent years, some of which have been found to play a crucial role in neoplastic processes and will profoundly change the nature of cancer treatment.
Abstract: A wide range of growth factors has been identified in recent years, some of which have been found to play a crucial role in neoplastic processes. Some tumours produce considerable amounts of these peptides and their requirement for growth factors is often much reduced leading to a degree of autonomy which may itself contribute to tumourigenicity. In addition, growth factors such as TGF-alpha, PDGF, FGF and IGFs have been found to be overexpressed in tumours. The growth factor effector pathway is thus open to intervention, e.g. by blocking the receptor using specific antibodies or interfering with posttranscriptional activation. This is even more evident as oncogenes such as erbB and v-sis encode for growth factor receptors. Soluble receptors, due to high affinity binding, might also be used to sequester growth factors from its specific membrane-bound receptors. Tyrosine-specific protein kinase activity may be inhibited by tyrosine analogues such as erbstatin or by more specific tyrosine-kinase inhibitors. Some therapeutical concepts have already been developed in clinical trials. Tumour necrosis factor (TNF) has successfully been used in extremity melanoma and sarcoma and monoclonal antibodies directed against the EGF receptor has also been applied in patients with advanced squamous lung cancer. Synthetic growth factor analogues which bind to the receptor without eliciting a signal may soon become a supplementary part in cancer treatment. Growth factor action is also blocked by suramin and its analogues and clinical phase I and II trials are underway. These novel therapeutical aspects will profoundly change the nature of cancer treatment.
64 citations
TL;DR: Natural killer cells are a distinct lymphocytic population, with the morphology of large granular lymphocytes, and they lack surface Ig or T-cell markers, so agents that inhibit the generation of reactive oxygen species may abrogate the suppression exerted on NK cells by monocytes/macrophages, therefore offering potential therapeutic benefit as immunoadjuvants.
64 citations
TL;DR: It is concluded that despite its strict conservation and universal post-translational modification, the histidine precursor of diphthamide is not essential to the function of yeast EF-2 in protein synthesis.
59 citations
TL;DR: Continuous efforts are being made to investigate molecules exclusively expressed on cancer cells, to improve the specificity and efficacy of these immunotoxins, and to eliminate side effects and improve pharmacokinetics and ensure better drug delivery.
58 citations