Special Lecture Oxazaphosphorine Cytostatics: Past-Present-Future Seventh Cain Memorial Award Lecture1

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Special Lecture Oxazaphosphorine Cytostatics: Past-Present-Future Seventh Cain Memorial Award Lecture1 [CANCER RESEARCH 49. 1-7. January I, 1989] Special Lecture Oxazaphosphorine Cytostatics: Past-Present-Future Seventh Cain Memorial Award Lecture1 NorbertBrock Department of Cancer Research, ASTA Pharma AG. D-4800 Bielefeld 14. Federal Republic of Germany lin. In the words of Heubner, "I love that word conscientiousness. Abstract It conveys the indispensable association between scientific knowl The development of the oxazaphosphorine cytostatics cyclophos- edge and responsibility—sdentici et conscientia"'. This was one phamide, ifosfamide, and trofosfamide was based on the idea of applying of the essential principles of Wolfgang Heubner at the Pharma the transport form/active form principle to the highly reactive nitrogen cology Institute of the University of Berlin, and I have attempted mustard group. A critical analysis and synopsis of the available results and knowledge will include examination of the extent to which the to base my life and work on this too. Hermann Druckrey was hypotheses on which this concept is based have been confirmed by responsible for my broad introduction to the fundamentals of experimental and clinical findings: pharmacology, and specifically to cancer research. He was one 1. Chemical synthesis succeeded in converting the reactive nitrogen of the founders of the field of oncological pharmacology, the mustard into an inactive transport form (latentiation). scientific basis of which he developed and considerably extended. 2. The requirement that the transport form be enzymatically activated Even in these early years in Berlin we were interested in drugs to to the active form in the target organ (the cancer cell) has been achieved inhibit cell division, and a particularly suitable subject for the by a sequence of metabolic reactions. systematic study of this was the fertilized sea urchin egg, being 3. The aim of considerably increasing the therapeutic index of alkyl- simple and not subject to pain. The results of these studies at the ating agents has been achieved by the oxazaphosphorine cytostatics. The Zoological Research Station in Naples with the support of the greater cancerotoxic selectivity is closely correlated with the cytotoxic specificity of their activated primary metabolites. greatly respected Reinhard Dohrn proved subsequently to be a 4. The cancerotoxic selectivity of oxazaphosphorines was further in useful basis for the chemotherapy research at ASTA. creased when mesna was introduced as a regional uroprotector. Mesna I became head of the Pharmacology Department of Asta- eliminates the risk of therapy-limiting urotoxic side effects of oxaza Werke in 1949. This allowed me to place my specialist's knowl phosphorines. With mesna protection, these cytostatics can be given in edge of pharmacology and internal medicine at the service of higher doses with increased safety, and their therapeutic efficacy can be versatile drug research and drug development. From the outset enhanced. our aim was not to leave the discovery of new drugs to chance 5. Stabilization of the primary oxazaphosphorines, e.g., by attaching but to base it on rational scientific hypotheses and to take account 2-mercaptoethanesulfonic acid (mafosfamide), opens up new possibilities of the results of biophysical and biochemical, as well as phar in preclinical investigations and in therapy, e.g., for the clonogenic stem macological and clinical, research. Together with Hermann cell assay, for in vitro purging in autologous bone marrow transplantation, for regional perfusion of tumors, and, in small doses, for immunomodu- Druckrey in Freiburg and Berthold Schneider in Hannover, we lation, where appropriate, in conjunction with "biological response mod developed the pharmacological and biometrie bases for the ifiers." screening and pharmacological characterization of new drugs. This included standardization of the experimental conditions for determination of chemical and biological activities in vitro. Op Introduction timization of the pharmacological testing in vivo was based on The great distinction conferred by the Cain Memorial Award the creation of adequate test models for determining the thera is evident from its stated objective "to give recognition for peutic and toxic effects, on the formulation of sharper action outstanding preclinical research leading to the discovery of a criteria, on the use of quantitative test methods, especially of the significant new therapeutic agent for the improved care of cancer dose-response analysis, and on the development of pharmaco- patients." It is thus a great pleasure for me to join the list of dynamic and pharmacokinetic investigation methods for the award winners, whose contributions are regarded as milestones determination of the cumulative properties. The evaluation was in the advance of cancer chemotherapy. based on the determination of the therapeutic index, of the The acknowledgement of the pharmacologist's work in the danger coefficient, and of the therapeutic units ( 1). development of the oxazaphosphorine cytostatics must take into Despite this good scientific basis, it was a very bold step for account a number of scientists from other specialties who, in the Asta-Werke, a medium-sized pharmaceutical company in Biele past, have made essential contributions, and it suggests that the feld, to have, in 1952, the chemist Herbert Arnold, the pharma future prospects in this area of research should be outlined: "To cologist Norbert Brock, and the clinician Hilmar Wilmanns, see the future requires the memory of the past".2 together with Ewald Kipper, the founder and then president of the company, decide to make the chemotherapy of malignant diseases a main aim of research. The prospects for the develop Environment and Personal Background ment of cancer chemotherapy were regarded in the early 1950's Among the personalities I remember with particular respect as rather poor, and the benefit/risk relation was generally assessed from the 1930's when I was becoming a physician and researcher as extremely unfavorable. To achieve a breakthrough it was are the physician Ernst Edens from Düsseldorfand the phar necessary in this area of drug therapy, more than in any other, macologists Wolfgang Heubner and Hermann Druckrey in Ber- to conduct long-term and high-level research and to provide sufficient finance, and the latter probably appeared at that time Received 5/24/88: revised 9/13/88: accepted 9/29/88. scarcely possible for a company of the size of Asta-Werke. Indeed ' Presented at the 79th Annual Meeting of the American Association for Cancer Research, May 25. 1988. New Orleans. LA. most research into cancer chemotherapy was then, worldwide, 2W. Düchting.personal communication. confined almost entirely to the large cancer research centers, 1 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1989 American Association for Cancer Research. OXAZAPHOSPHORINE CYTOSTATICS which received governmental support; only a few pharmaceutical Oxazaphosphorine Cytostatics companies were carrying out their own cancer research. Asta- After the success of fosfestrol, our team, including Arnold, Werke has kept faith with its decision for more than 35 years Bourseaux, and Wilmanns, tried to apply the transport form/ now, the only pharmaceutical company in Germany to do so. active form principle to the group of alkylating nitrogen mus To gain this objective it was necessary to have a group of tards. The structure of these compounds appeared to be partic workers able to see and to some extent master the problems in ularly suitable for designing a prodrug (5). Their cytotoxic action this area. ASTA then had had competent chemical, pharmaco is closely related to the reactivity of the 2-chloroethyl groups, logical, and clinical research departments. For experimental on which in turn is linked with the basicity of the central nitrogen cology, immunology, biochemistry, and biometry we sought atom. Thus, chemical synthesis can be used to alter the reactivity cooperations with universities who provided continuous concep of the functional groups in a specific manner. Ishidate et al. (6) tual and methodological support. Thus, our research group can were the first to demonstrate this relationship by describing be regarded as an early and very efficiently functioning model of chlormethine TV-oxideas an antitumor drug. targeted collaboration between researchers in industry and the One of the earliest attempts to utilize chemically derived universities, and I would like to pay a grateful tribute to the structural variations of the nitrogen mustard molecule for the pharmacologist and oncologist Hermann Druckrey of Freiburg, the biochemist Hans-JürgenHohorst of Frankfurt, the micro- synthesis of compounds with greater tumor selectivity was the work of Friedman and Seligman with open-chain phosphor- biologist and immunologist JürgenPotei of Bielefeld and Han amide mustard compounds (7). These compounds are chemically nover, and the biometrician Berthold Schneider of Hannover for stable but, according to our own experiments (8), unsuitable as many years of friendly cooperation. substrates for enzymatic activation; their oncocidal efficacy was insufficient, resulting in a narrow therapeutic range. Cyclophosphamide. Our approach was aimed at obtaining Transport Form/Active Form as a Therapeutic Principle cyclic TV-phosphorylation products of «or-nitrogen mustard as prodrugs. These chemically and pharmacologically inactive We were aware from the outset that, in view of the financial transport forms should
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