Structure—activity relationships in diphtheria toxin and Pseudomonas aeruginosa exotoxin A

Collier, R. J.

doi:10.1007/978-1-4613-1083-9_3

Cited by 26 publications

(12 citation statements)

References 48 publications

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“…PE is one of the most common toxins used as toxin moiety in targeted cancer therapy. The reasons for that are that PE is one of the most investigated toxins and is easy to produce in E. coli [15,[27][28][29][30][31][32][33]. Another important feature of PE is that it withstands many mutations without harming its toxicity.…”

Section: Pseudomonas Exotoxin A-based Immunotoxinsmentioning

confidence: 99%

Antibody-Based Immunotoxins for the Treatment of Cancer

Becker

Benhar

2012

Antibodies

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Antibody-based immunotoxins comprise an important group in targeted cancer therapeutics. These chimeric proteins are a form of biological guided missiles that combine a targeting moiety with a potent effector molecule. The targeting moiety is mostly a monoclonal antibody (MAb) or a recombinant antibody-based fragment that confers target specificity to the immunotoxin. The effector domain is a potent protein toxin of bacterial or plant origin, which, following binding to the target cells, undergoes internalization and causes cell death. Over time and following research progression, immunotoxins become better fitted to their purpose, losing immunogenic fragments and non-specific targeting moieties. Many immunotoxins have gone through clinical evaluation. Some of these have been shown to be active and work is progressing with them in the form of further clinical trials. Others, mostly developed in the previous century, failed to generate a response in patients, or even caused undesired side effects. This article reviews the antibody and protein-toxin based immunotoxins that were clinically evaluated up to the present day.

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Section: Pseudomonas Exotoxin A-based Immunotoxinsmentioning

confidence: 99%

Antibody-Based Immunotoxins for the Treatment of Cancer

Becker

Benhar

2012

Antibodies

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“…This hypothesis was further supported by results of kinetic experiments, which showed that AZT reduced the PE-, but not RIC-, induced firstorder inhibition of protein synthesis when added during the first-order decline. Our finding that AZT blocked the PE-catalyzed events was surprising, as AZT treatment did not significantly block DT toxicity in Vero or CHO cells, despite the fact that both toxins ADP-ribosylate the same diphthamide residue in elongation factor-2 (Collier, 1988;Omura et al, 1989). Our ability to detect the AZT inhibition of PE, but not DT, cytotoxicity was apparently due to the fact that AZT blocked the PE inhibition of protein synthesis more effectively than it blocked the same inhibition by DT.…”

Section: Effects Of Various Agents On the Azt Inhibitionmentioning

confidence: 74%

Characterization of 3′‐azido‐3′‐deoxythymidine inhibition of ricin and pseudomonas exotoxin A toxicity in CHO and vero cells

Wellner¹,

Pless²,

Thompson³

1994

Journal Cellular Physiology

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Ricin (RIC), modeccin (MOD), Pseudomonas exotoxin A (PE), and diphtheria toxin (DT) are protein toxins that enter cells by receptor-mediated endocytosis. After intracellular transport and membrane translocation to the cytosol, these toxins inhibit protein synthesis by enzymatically removing a specific adenine residue from ribosomal RNA (RIC, MOD), or by ADP-ribosylation of elongation factor-2 (PE, DT). Recently, Thompson and Pace (1992) reported that AZT (3'-azido-3'-deoxythymidine) inhibited RIC toxicity in Vero cells, and this inhibition was not due to a block of RIC enzymatic activity. This paper extends these findings and examines the effects of AZT treatment on the toxicities of other protein toxins in Chinese hamster ovary (CHO) and Vero cell lines. AZT treatment did not significantly alter the toxicity of DT or MOD in either cell line, but it markedly reduced RIC and PE toxicity in both cell lines. The ID50 values (concentration of toxin required to inhibit protein synthesis by 50%) for RIC and PE in CHO cells increased approximately 6.5- and 12.5-fold, respectively; while in Vero cells the ID50 values increased ca. 8.5- and 4.5-fold, respectively. Results of further studies revealed differences in the mechanisms by which AZT inhibited RIC and PE toxicity. Results of cell-free translation indicated that, unlike its effects on RIC, AZT blocked the ability of PE to perform its enzymatic activity. As AZT did not block RIC enzymatic activity, we examined the effects of AZT on earlier steps in the RIC intoxication process. AZT treatment did not inhibit cell-surface binding or internalization of [125I]-RIC. Results of kinetic studies showed that when AZT was incubated with cells at the time of RIC exposure, it caused no major change in the lag phase, during which RIC reaches the site of translocation. However, it clearly reduced the subsequent first-order reduction in the rate of protein synthesis, suggesting an effect on translocation. Monensin (an ionophore that perturbs intracellular trafficking and increases the toxicities of RIC and PE) reduced AZT protection against both toxins. Nocodazole and colchicine (agents that disrupt microtubules and some routes of intracellular trafficking) reduced the ability of AZT to inhibit RIC, but not PE, toxicity. In summary, our results suggest that (1) AZT acts within the cytosol to inhibit (directly or indirectly) the enzymatic action of PE, and (2) the AZT inhibition of RIC cytotoxicity does not involve perturbations of RIC cell-surface binding, internalization, or enzymatic activity but might result from an alteration in RIC translocation.

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“…As described, once delivered to IL-2R bearing cells, PE and DT ADP-ribosylate and inactivate EF-2 in the cytosol, leading to apoptosis and cell death (Fig. 4) [151,[162][163][164][165][166].…”

Section: Chimeric Il-2 Toxin Biologicsmentioning

confidence: 86%

“…Targeting EF-2 for inactivation, PE and DT stall protein synthesis and lead to cell death via apoptosis (Fig. 4) [151,[162][163][164][165][166]. In several in vitro cell culture systems and animal models of cancer for leukemias, lymphomas, carcinomas and GvHD, these bacterial toxins have been tested to determine their effectiveness as anti-tumor and immunosuppressive recombinant biologics.…”

Section: Recombinant Bacterial Immunotoxinsmentioning

confidence: 99%

IL-2 Receptor Targeted Immunomodulatory Biologics: The Past, Present, and Future

Franke¹,

Shirwan²

2006

CIR

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The interleukin-2 (IL-2) and interleukin-2 receptor (IL-2R) system plays a central role in both the innate and adaptive arms of the immune response. Of major importance is the function of IL-2/IL-2R in the activation, differentiation, expansion, and maintenance of T cells that are critical to adaptive immunity. Clinically, the IL-2/IL-2R axis has been linked to the development and persistence of hematopoietic malignancies, autoimmune disorders, and allograft rejection. As such, the IL-2/IL-2R system has been extensively studied and exploited for T-cell directed immunotherapy. Several immunomodulatory approaches targeting this receptor system have been developed that include antibody-based ligands and radioisotopes, as well as immunoglobulin and cytokine chimeric biologics, which contain toxins and apoptosis-inducing proteins. While some of these biologics are already in clinical practice others are either in transition to the clinic or under development. We herein review the effectiveness and limitations of these biologics and discuss new strategies that could minimize the limitations and improve on the efficacy of IL-2R-targeted immunotherapy.

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Structure—activity relationships in diphtheria toxin and Pseudomonas aeruginosa exotoxin A

Cited by 26 publications

References 48 publications

Antibody-Based Immunotoxins for the Treatment of Cancer

Antibody-Based Immunotoxins for the Treatment of Cancer

Characterization of 3′‐azido‐3′‐deoxythymidine inhibition of ricin and pseudomonas exotoxin A toxicity in CHO and vero cells

IL-2 Receptor Targeted Immunomodulatory Biologics: The Past, Present, and Future

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