Amethopterin: A Toxic Tumour Growth Inhibitor

Jg, Bennette

doi:10.1038/bjc.1952.42

Cited by 7 publications

(6 citation statements)

References 9 publications

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“…Später wurde bei der Einführung der Chemotherapie festgestellt, dass sich Krebszellen schneller vermehren als normale Zellen, eine Tatsache, die die Chemotherapie zu einer praktikablen Alternative zur Behandlung von Krebs machte, wenn auch zum Preis von Nebenwirkungen unterschiedlicher Schwere für den Patienten. Zu den frühen zytotoxischen Wirkstoffen gehören Mechlorethamin (N‐Lost, Chlormethin), eine Verbindung die ursprünglich für die chemische Kriegsführung entwickelt wurde, der Folsäureantagonist Amethopterin (Methotrexat), der antileukämische Antimetabolit 6‐Mercaptopurin und die Vinca‐Alkaloide (z. B. Vincristin), letztere üben ihre zytotoxische Wirkung aufgrund ihrer inhibitorischen Aktivität auf die Mikrotubulipolymerisation aus.…”

Section: Eine Kurze Geschichte Von Krebstherapien Und Der Entstehung unclassified

Die Bedeutung der organischen Synthese bei der Entstehung und Entwicklung von Antikörper‐Wirkstoff‐Konjugaten als gezielte Krebstherapien

Nicolaou

Rigol

2019

Angewandte Chemie

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Mit einigen Antikörper‐Wirkstoff‐Konjugaten (ADCs), die für den klinischen Einsatz als zielgerichtete Krebstherapien zugelassenen sind, und zahlreichen Kandidaten in klinischen Studien, entwickelt sich das Gebiet der ADCs zu einem hochaktuellen biomedizinischen Forschungsfeld, insbesondere im Bereich der Krebsbehandlung. Chemiker, Biologen und Mediziner kombinieren ihre Expertisen, um Design, Synthese, Wirksamkeit und Präzision zu verbessern, während sie danach streben, dieses Grundprinzip der personalisierten und zielgerichteten Medizin voranzutreiben, um Krebspatienten effektiver zu behandeln und ihren Anwendungsbereich auf andere Indikationen auszudehnen. So wie Alexander Flemings Penicillin und die unzähligen anderen bioaktiven Naturstoffe, die auf dessen Entdeckung und seinen Erfolg in der Klinik folgten, nach dem Zweiten Weltkrieg eine Revolution in der Medizin auslösten, so haben Calicheamicin γ1I und andere hochwirksame, natürlich vorkommende Antitumorverbindungen ebenso eine zentrale Rolle gespielt, wenn es darum geht, die Einführung dieses neuen Konzepts der medizinischen Intervention “biologisch‐niedermolekularer Hybride” zu ermöglichen. Heute gibt es vier klinisch zugelassene Medikamente des ADC‐Konzepts: Mylotarg, Adcetris, Kadcyla und Besponsa, von denen das erst‐ sowie das letztgenannte den gleichen von Calicheamicin γ1I abgeleiteten Wirkstoff tragen. Dieser Aufsatz deckt onkologische Anwendungen ab und konzentriert sich nach einer kurzen Geschichte der Entstehung des Bereichs der ADCs, welcher vor mehr als einem Jahrhundert durch Paul Ehrlichs Konzept der Zauberkugel begründet wurde, in erster Linie auf die Aspekte der chemischen Synthese des multidisziplinären Forschungsunternehmens der ADCs.

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Section: Eine Kurze Geschichte Von Krebstherapien Und Der Entstehung unclassified

Die Bedeutung der organischen Synthese bei der Entstehung und Entwicklung von Antikörper‐Wirkstoff‐Konjugaten als gezielte Krebstherapien

Nicolaou

Rigol

2019

Angewandte Chemie

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“…The results, however, are complicated by the toxicity of these two folic acid antagonists, although a wide variation in susceptibility has been encountered. Bennette (1952), in experiments with A-methopterin in mice, concluded that the association between the toxicity and tumour growth inhibition was so close that no confidence could be placed in the selectivity of the drug against certain sarcomata. Our results, in part, tend to confirm this conclusion-especially when the drugs are administered intraperitoneally to very young chicks.…”

Section: Resultsmentioning

confidence: 99%

“…was given intraperitoneally each day. Bennette (1952), in experiments with A-methopterin in mice, concluded that the association between the toxicity and tumour growth inhibition was so close that no confidence could be placed in the selectivity of the drug against certain sarcomata. Our results, in .421…”

Section: Methodsmentioning

confidence: 99%

“…The toxic effects encountered in our experiments were poor growth, anaemia and leucopenia, and death. Bessis and Freixa (1950) This toxicity could be counteracted by citrovorum factor administered intraperitoneally, but any tumour-inhibiting action was neutralized.…”

Section: Methodsmentioning

confidence: 99%

“…The mean time of first appearance of the tumour in the survivors was also greater in the chicks receiving aminopterin, but the tumour incidence in both the medicated and control groups was 100%. Bessis and Freixa (1950) found that aminopterin and A-methopterin offered partial protection against a transmissible erythroblastosis in young chicks, but some intoxication was encountered. Ringsted (1953) showed that aminopterin in a chick mash at levels of 5, 10, 20 and 40 mg./kg.…”

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confidence: 99%

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FURTHER OBSERVATIONS ON THE EFFECT OF AMINOPTERIN, A‐METHOPTERIN AND CITROVORUM FACTOR ON THE GROWTH OF TRANSPLANTABLE AVIAN LYMPHOID TUMOURS

Chubb

Laursen

1954

British Journal of Pharmacology and Chemotherapy

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A number of workers have reported on the effect of aminopterin and A-methopterin on the course of the growth of the Rous sarcoma and certain transmissible tumours in chicks. Woll (1948) and Little, Sampath, Paganelli, Locke and Subbarow (1948) have shown that a number of folic acid antagonists completely or partly inhibit the growth of the Rous chicken sarcoma although some toxic effects were encountered. The latter workers showed that the toxicity of aminopterin, in particular, could be partially neutralized by either pteroyldi-or pteroyltriglutamic acid in a 25 to 1 ratio, but such mixture showed no virusinhibiting effect. Stock, Biesele, Burchenal, Karnofsky, Moore and Sugiura (1950) have also demonstrated that several analogues of folic acid exert an adverse effect upon tumour tissue. Ringsted (1952) fed a balanced chick mash containing aminopterin (5 mg./kg. of food) and found that the survival rate of chicks inoculated with Rous sarcoma was significantly higher at the end of the first week compared with that of chicks receiving no drug. The mean time of first appearance of the tumour in the survivors was also greater in the chicks receiving aminopterin, but the tumour incidence in both the medicated and control groups was 100%. Bessis and Freixa (1950) found that aminopterin and A-methopterin offered partial protection against a transmissible erythroblastosis in young chicks, but some intoxication was encountered. Ringsted (1953) showed that aminopterin in a chick mash at levels of 5, 10, 20 and 40 mg./kg. increased the mean induction time of a Mill Hill endothelioma in young chicks. The two higher levels proved toxic, and the drug at all levels had no effect on the total number of takes and subsequent growth-rate of the tumours. Darcel (1953a) failed to show any increase in the time taken for tumours to appear when aminopterin or A-methopterin were given orally to chicks bearing tumour strain RPL 12. The drugs were administered directly into the crop in aqueous suspensions (0.1 and 1.0 mg. of each drug/day). No toxic symptoms were reported.Recently, citrovorum factor, a substance closely related to folic acid, has been found to be many times more effective than folic acid itself in reversing the toxicity of folic acid antagonists in the rat, chick, and man, and in this paper a number of observations are presented on the effect of aminopterin, A-methopterin and synthetic citrovorum factor on the growth of transplantable lymphoid tumour strains isolated from cases of avian leukosis. METHODSThe general characteristics of the tumour strains used in the present study, RPL 12 and 19, have been described by Darcel (1953b). A tumour develops at the site of inoculation followed by rapid metastasis, in the absence of leukaemia, to the viscera, especially the liver.Crossbred (B.R. X Br.L. and B.R. x W.L.) chicks were inoculated with tumour cell suspensions either at two or seven days of age. The birds were maintained in small metal cages and fed freely on a balanced chick mash.The tumour cell suspensions were prepa...

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The Role of Organic Synthesis in the Emergence and Development of Antibody–Drug Conjugates as Targeted Cancer Therapies

Nicolaou

Rigol

2019

Angew Chem Int Ed

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With a number of antibody–drug conjugates (ADCs) approved for clinical use as targeted cancer therapies and numerous candidates in clinical trials, the field of ADCs is emerging as one of the frontiers in biomedical research, particularly in the area of cancer treatment. Chemists, biologists and clinicians, among other scientists, are partnering their expertise to improve their design, synthesis, efficacy and precision as they strive to advance this paradigm of personalized and targeted medicine to treat cancer patients more effectively and to expand its scope to other indications. Just as Alexander Fleming's penicillin, and the myriad other bioactive natural products that followed its discovery and success in the clinic, ignited a revolution in medicine after the Second World War, so did calicheamicin γ1I, and other highly potent naturally occurring antitumor agents, play a pivotal role in enabling the advent of this new paradigm of “biological‐small molecule hybrid” medical intervention. Today there are four clinically approved drugs from the ADC paradigm, Mylotarg, Adcetris, Kadcyla and Besponsa, in order of approval, the first and the last of which carry the same calicheamicin γ1I‐derived payload. Covering oncological applications, and after a brief history of the emergence of the field of antibody–drug conjugates triggered more than a century ago by Paul Ehrlich's “magic bullet” concept, this Review is primarily focusing on the chemical synthesis aspects of the ADCs multidisciplinary research enterprise.

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Amethopterin: A Toxic Tumour Growth Inhibitor

Cited by 7 publications

References 9 publications

Die Bedeutung der organischen Synthese bei der Entstehung und Entwicklung von Antikörper‐Wirkstoff‐Konjugaten als gezielte Krebstherapien

Die Bedeutung der organischen Synthese bei der Entstehung und Entwicklung von Antikörper‐Wirkstoff‐Konjugaten als gezielte Krebstherapien

FURTHER OBSERVATIONS ON THE EFFECT OF AMINOPTERIN, A‐METHOPTERIN AND CITROVORUM FACTOR ON THE GROWTH OF TRANSPLANTABLE AVIAN LYMPHOID TUMOURS

The Role of Organic Synthesis in the Emergence and Development of Antibody–Drug Conjugates as Targeted Cancer Therapies

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