From Atoxyl to Salvarsan: Searching for the Magic Bullet

Riethmiller, S.

doi:10.1159/000087453

Cited by 58 publications

(47 citation statements)

References 18 publications

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“…606 had a major curative potential in rabbits infected with T. pallidum , without producing intolerable toxicity (table 3). Thus, they had discovered a magic bullet to treat syphilis: arsphenamine (Salvarsan®) [36,37,38]. …”

Section: Successful Translation - the Case Of Salvarsanmentioning

confidence: 99%

Paul Ehrlich (1854-1915) and His Contributions to the Foundation and Birth of Translational Medicine

Valent

Groner²,

Schumacher³

et al. 2016

J Innate Immun

274

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Translational research and precision medicine are based on a profound knowledge of cellular and molecular mechanisms contributing to various physiologic processes and pathologic reactions in diverse organs. Whereas specific molecular interactions and mechanisms have been identified during the past 5 decades, the underlying principles were defined much earlier and originate from to the seminal observations made by outstanding researchers between 1850 and 1915. One of the most outstanding exponents of these scientists is Paul Ehrlich. His work resulted not only in the foundation and birth of modern hematology and immunology, but also led to the development of chemotherapy and specific targeted treatment concepts. In 2015, the Medical University of Vienna organized a memorial meeting, with the aim of honoring Paul Ehrlich's contributions to science, and to commemorate the 100th anniversary of his death. The authors of the current review served as faculty members and dedicate this paper to Paul Ehrlich and his remarkable contributions to medicine.

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Section: Successful Translation - the Case Of Salvarsanmentioning

confidence: 99%

Paul Ehrlich (1854-1915) and His Contributions to the Foundation and Birth of Translational Medicine

Valent

Groner²,

Schumacher³

et al. 2016

J Innate Immun

274

View full text Add to dashboard Cite

show abstract

“…He is very good at staining, but he will never pass his examinations' [4,5] . Ehrlich's doctoral dissertation dealt with theoretical and practical aspects of histological stains, and he experimented with the recently discovered aniline-derived dyes [6][7][8][9][10] . Upon observing that the uptake of different dyes varied in different tissues, he concluded that strong affinities must exist between biological structures and the stain applied.…”

Section: Early Work and Initial Challengesmentioning

confidence: 99%

“…3 a). This new formula suggested other routes by which its chemical structure could be modified, and a number of derivatives were subsequently synthesized with the aim of enhancing its therapeutic efficacy [4,5,9] .…”

Section: Structure-activity Relationships: the Case Of Arsenicalsmentioning

confidence: 99%

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The Contributions of Paul Ehrlich to Pharmacology: A Tribute on the Occasion of the Centenary of His Nobel Prize

2008

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On the centenary of Paul Ehrlich’s Nobel Prize, this German researcher deserves to be remembered as a pioneer in a large number of scientific disciplines. As a result of his enthusiasm and scientific abilities, dedication, and contacts with other scientists of his time, he was able to make countless contributions in fields as diverse as histology, haematology, immunology, oncology, microbiology and pharmacology, among others. Although the Swedish award was meant to recognize the standardization of the manufacture of antidiphtheria serum, it was the discovery of arsphenamine (Salvarsan) for the treatment of syphilis which won him wider international acclaim. From a pharmacological perspective, Ehrlich’s outstanding contributions include dissemination of the ‘magic bullet’ concept for the synthesis of antibacterials, introduction of concepts such as chemoreceptor and chemotherapy, and linking the chemical structure of compounds to their pharmacological activity. These achievements took place within the framework he established for the transition from experimental pharmacology to therapeutic pharmacology. He introduced a modern research system based on the synthesis of multiple chemical structures for pharmacological screening in animal models of disease states. These contributions were undoubtedly decisive in propitiating the wider development of antibiotics decades later. For these reasons, it is fitting to mark the 100th anniversary of the Nobel Prize awarded to this great scientist by commemorating the importance of his contributions to the advance of pharmacology.

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“…His work on staining microorganisms and cells with aniline dyes led him to propose that chemical substances might have special affi nities for cancer cells. Th ese substances should act as "Magic Bullets" by going straight to the cells at which they were aimed and killing them (51). Th e continued joint eff ort of basic and clinical scientists that so successfully produced trastuzumab and the newer TKIs, will hopefully help improve the effi cacy of these ErbB2 targeted "Magic Bullets".…”

Section: Clinical Development Of Erbb2 Inhibitors: Perspectives and Fmentioning

confidence: 99%

ErbB Receptors in Cancer: HER2/ErbB2 as a Therapeutic Target

Ne¹

2008

AACR Education book

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In the mid-1980s, amplifi cation of the gene encoding ErbB2/HER2 was the fi rst consistent genetic alterations detected in human breast tumors (1, 2). ErbB2/HER2 belongs to the epidermal growth factor (EGF/ErbB) family of receptor tyrosine kinases (RTK). Th e ErbB2 amplicon on chromosome 17q12-21, which is detected in approximately 20% of breast tumors, correlates with dramatic overexpression of the receptor. Soon after discovery of ErbB2 gene amplifi cation it was recognized that patients with elevated receptor levels had a poor clinical prognosis (reviewed in (3, 4) ). Since then, ErbB2/HER2 has been intensely studied not only to understand its role in cancer biology but also to target the receptor with anti-cancer therapeutics. Currently, various ErbB2/HER2 targeted inhibitors area in clinical use. Th ese include the monoclonal antibodies trastuzumab and pertuzumab that bind the receptor's extracellular domain, and small molecule tyrosine kinase inhibitors that inhibit the enzymatic activity of the kinase domain. In this review our understanding of how ErbB2 receptor are activated and contribute to cancer development will be described. Furthermore, the development of anti-ErbB2/HER2 targeted therapeutics for clinical use will be discussed taking into consideration the current views on their mechanism of action. Potential mechanisms that underlie a successful clinical response to inhibition of ErbB2, as well as possible reasons for non-response will also be discussed. ErbB Receptor PathwayErbB Receptor Activation ErbB2/HER2 belongs to the EGF/ErbB family of RTK, which also includes EGFR/ ErbB1, HER3/ErbB3 and HER4/ErbB4. Th e various names for the receptors refl ect their discovery in diff erent organisms and I will refer to them as the ErbB receptor family (EGFR, ErbB2, ErbB3 and ErbB4) throughout this review. Each of the receptors has an extracellular ligand binding region, a single membrane spanning region and a cytoplasmic tyrosine kinase containing domain.Th e EGF-family of peptides bind the ErbB receptors and based upon their receptor specifi city are divided into three groups. Th e fi rst group includes EGF, transforming growth factor (TGF)-α, amphiregulin (AR) and epigen (EPG), which bind specifi cally to EGFR; the second group includes betacellulin (BTC), heparin-binding EGF (HB-EGF) and epiregulin (EPR), which exhibit dual specifi city, binding both EGFR and ErbB4. Th e third group, composed of the neuregulins (NRGs), forms two subgroups based upon their capacity to bind ErbB3 and ErbB4 (NRG-1 and NRG-2) or only ErbB4 (NRG-3 and NRG-4) (5, 6). Ligand binding to

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From Atoxyl to Salvarsan: Searching for the Magic Bullet

Cited by 58 publications

References 18 publications

Paul Ehrlich (1854-1915) and His Contributions to the Foundation and Birth of Translational Medicine

Paul Ehrlich (1854-1915) and His Contributions to the Foundation and Birth of Translational Medicine

The Contributions of Paul Ehrlich to Pharmacology: A Tribute on the Occasion of the Centenary of His Nobel Prize

ErbB Receptors in Cancer: HER2/ErbB2 as a Therapeutic Target

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