Kurt Hellmann

Kurt Hellmann (May 12, 1922 – April 2, 2013) was a clinical pharmacologist with an outstanding record in translational medicine. He discovered the biologic activity of two important drugs: Razoxane & Dexrazoxane

Early career

Kurt Hellmann was born in Nürnberg, Bavaria, in May 12, 1922, where he attended primary school from 1927 to 1932 and the first year of the ‘Reformgymnasium’ before having to emigrate as a 10-year-old boy with his parents and his elder brother to England in March 1933. After finishing school in London he served during wartime as an engineer. After the war he studied chemistry in London. Between 1950 and 1957 he continued his academic career at the Department of Anatomy in Oxford and concurrently at the Physiological Institute of the Royal Navy in Oxford and Singapore. He earned a Ph.D. in Pharmacology (1953), a BM ChB in Medicine (1958) and a D.M. degree (1964) at Magdalen & Balliol College Oxford where he won the prestigious Radcliffe Prize for Medical Research for his histochemical investigations on cholinesterase and amine oxidase in the skin.[1]

Discovery

Inspired research and a close eye for detail led the UK clinician and pharmacologist Kurt Hellmann to discovery of the unique cytostatic, cytoprotective and antimetastatic biological activities of bisdioxopiperazines in his laboratory at ICRF's Cancer Chemotherapy Unit in the early 1970s.These agents were synthesised as derivatives of EDTA by the ICRF chemist Andrew Creighton and their characteristics and chemistry were excellently summarized by Eugene Herman in 1982.[2] Following Karrer, Goldin and Humphreys' description of the Lewis lung (3LL) carcinoma as a model for metastases Hellmann set up the 3LL as a screen for antimetastatic compounds in 1968. The first compound to be tested in this first antimetastatic drug screen was the cytostatic agent razoxane [ICRF 159]. As serendipity would have it, it showed almost total suppression of metastases without seeming to affect the growth of the primary implant, thus making razoxane the first fully antimetastatic drug.This work was regarded as a major breakthrough when published in a landmark paper in the BMJ in early 1972.[3] This study, by Le Serve & Hellmann clearly showed for the first time that a drug which 'normalised the tumour-induced pathologic vasculature', in that it blocked intra-tumoural haemorrhage and hence the spread of cancer cells, prevented lethal metastasis.Such an observation pre-dated by many years the current interest in conversion of tumour vasculature to a more normal morphology and function as a therapeutic approach. In the clinical context the orally active Razoxane subsequently was shown to prevent liver metastases in adjuvant treatment of colorectal cancer.[4] More recently it has been demonstrated to potentiate certain schedules of chemoradiotherapy and suppress metastasis in soft tissue sarcomas,in part by improvement of oxygen and drug delivery.[5]

In the early 1970s, Hellmann brought Razoxane to the attention of Abraham Goldin and Eugene Herman who found this intracellular active chelator to be highly effective in reducing anthracycline-induced cardiotoxicity in all species tested.[6] This led to a rapid NCI-supported clinical development of the parenteral, highly water-soluble pure enantiomer (+) Dexrazoxane [ICRF 187] by James Speyer (published in 1988/92)[7] and by Sandra Swain (published in 1997/98).[8] These pivotal prospective clinical studies clearly demonstrated effective, long-term cardioprotection by Dexrazoxane preserving the myocardial reserves in breast cancer patients with no additional toxicities and no reduced anticancer activity. Currently Dexrazoxane is the only FDA/EMA approved agent for preventing anthracycline-induced cardiotoxicity which according to Ewer & Speyer 'must become an essential part of anthracycline-based modern chemotherapy practice'[9] allowing for the optimization of anthracycline-based treatment modalities in adult and pediatric oncology without enhancing second malignancies.[10] This was also shown by Steven Lipshultz et al. in randomised, controlled clinical trials in long-term surviving children and adolescents in pediatric oncology.[11]

Breakthrough Translational Metastasis Research

After clinical training at the Radcliffe Infirmary, Oxford (1958–60) he joined Reckitt & Sons, Hull, to lead its Department of Pharmacology but was seconded to undertake medical research at the Department of Pharmacology, Royal College of Surgeons, London. In 1962 he became Director of the newly formed Department of Cancer Chemotherapy at the Imperial Cancer Research Fund London (ICRF; now the Cancer Research UK London Research Institute)—a post which he held until 1987 alongside clinical activities as an Honorary Consultant & Visiting Professor at the Radiotherapy & Oncology Department, Westminster Hospital, London (now Imperial College) from 1972 to 1993. In March 1974, Kurt Hellmann founded with his co-editor Stephen Carter (Director of the Division of Cancer Treatment, US National Cancer Institute) the highly regarded journal ‘Cancer Treatment Reviews’ which he edited from volume 1(1), 1974 to volume 18(4) in December 1991. With Stephen Carter and his clinical research fellow Marie Bakowski he published ‘Chemotherapy of Cancer’ in 1977 a convenient reference and guidebook for practising medical oncologists which ran through several editions.[12] In March 1974 he organized the first meeting of the E.O.R.T.C. Metastasis Club which he founded together with Silvio Garattini, Director of the Mario Negri Institute for Pharmacological Research, Milan. In the early 1980s the ever-expanding interest in the field of metastasis led to the ‘Metastasis Research Society’. Its first international meeting was organised by Kurt Hellmann and Suzanne Eccles in London, in 1984 shortly after the inauguration of the Society's official journal ‘Clinical & Experimental Metastasis’ with Kurt Hellmann and co-editor Garth Nicolson.

Personal and later life

In 1972 Kurt Hellmann acted as Chairman of the British Association of Cancer Research (BACR) and gave the ‘Erasmus Wilson Lecture’ of the Royal College of Surgeons. When the Queen opened a new wing at ICRF's Lincoln's Inn site in 1973 he was given the task of showing her around the Department of Cancer Chemotherapy in which she took great interest. Following the Royal visit he received an invitation to lunch at the Palace. 'His happiness was boundless', his lifelong and affectionate friend Dr. Edwin Field remembered, 'as he loved England and was grateful that this country had offered him and his family a haven from German persecution'. Some 10 years later, as President of the Oncology Section of the Royal Society of Medicine, London, he was invited to give the ‘Haddow Lecture’ of BACR. Kurt Hellmann also made an memorable debut in ‘A Career in Pharmacology’ in 1961 filmed by members of staff of the Department of Pharmacology at the Royal College of Surgeons of England,then based at Examination Hall, Queen Square London, co-starring with the later Nobel Prize winner John Vane and others (Wellcome Trust, re-edited DVD, 2009). The Wellcome Library also holds a recording of a 1993 interview between Kurt Hellmann and two other colleagues remembering Sir Stanford Cade (1895–1973).[13] Cade was a pioneer in radiotherapy at the Westminster Hospital and an Air Vice Marshall of the Royal Airforce whose invaluable collection of case summaries was rescued by Hellmann upon the closure of the Westminster Hospital and given to the Contemporary Medical Archives Centre of the Wellcome Trust’s Library (GC147). The published proceedings of ‘The Stanford Cade Symposium’ organized by Kurt Hellmann at the Royal Institution, London, in 1973 bear witness to his early interests in preserving our medical heritage.

Kurt Hellmann continued to be active as a writer, advisor, critical discussant with his last letter to the JCO published on April 1, 2013.[14] A book edited by Hellmann and his colleague Walter Rhomberg in 2011 bears witness to the remarkable experimental and clinical adventure of "Razoxane and Dexrazoxane - Two Multifunctional Agents" as experienced by some of its key investigators.[15] A fuller account of Hellmann’s life and career was published as a 90th birthday tribute in Clinical & Experimental Metastasis, the scientific journal he served as valued founding and emeritus editor until his death.[16] Upon his death tributes from colleagues and friends around the world attested the outstanding impact of this 'rare breed of medical and scientific humanitarian' and his unwavering support for research careers and educational societies such as the Royal Society of Medicine (RSM), London.

Kurt Hellmann died in April 2, 2013 at the age of 90 in Withyham, East Sussex, UK. A Service of Thanksgiving was held at the Church of St.Michaels and All Angels, Withyham, April 19, 2013 for family and friends with donations to the RSM.[17]

References

  1. ↑ HELLMANN K (September 1955). "Cholinesterase and amine oxidase in the skin: a histochemical investigation". The Journal of Physiology. 129 (3): 454–63. PMC 1365976Freely accessible. PMID 13264109.
  2. ↑ Herman EH, Witiak DT, Hellmann K, Waravdekar VS (1982). "Biological properties of ICRF-159 and related bis(dioxopiperazine) compounds". Advances in Pharmacology and Chemotherapy. 19: 249–90. doi:10.1016/s1054-3589(08)60025-3. PMID 6819768.
  3. ↑ Le Serve AW, Hellmann K (March 1972). "Metastases and the normalization of tumour blood vessels by ICRF 159: a new type of drug action". British Medical Journal. 1 (5800): 597–601. doi:10.1136/bmj.1.5800.597. PMC 1787556Freely accessible. PMID 4111169.
  4. ↑ HHellmann K, Gilbert J, Evans M, Cassell P, Taylor R (1987). "Effect of razoxane on metastases from colorectal cancer". Clinical & Experimental Metastasis. 5 (1): 3–8. doi:10.1007/bf00116620. PMID 3829494.
  5. ↑ Rhomberg W, Wink A, Pokrajac B, et al. (May 2009). "Treatment of vascular soft tissue sarcomas with razoxane, vindesine, and radiation". International Journal of Radiation Oncology, Biology, Physics. 74 (1): 187–91. doi:10.1016/j.ijrobp.2008.06.1492. PMID 19004568.
  6. ↑ Herman EH, Ferrans VJ (August 1998). "Preclinical animal models of cardiac protection from anthracycline-induced cardiotoxicity". Seminars in Oncology. 25 (4 Suppl 10): 15–21. PMID 9768819.
  7. ↑ Speyer JL, Green MD, Sanger J, et al. (September 1990). "A prospective randomized trial of ICRF-187 for prevention of cumulative doxorubicin-induced cardiac toxicity in women with breast cancer". Cancer Treatment Reviews. 17 (2-3): 161–3. doi:10.1016/0305-7372(90)90041-d. PMID 2125531.
  8. ↑ Swain SM, Vici P (January 2004). "The current and future role of dexrazoxane as a cardioprotectant in anthracycline treatment: expert panel review". Journal of Cancer Research and Clinical Oncology. 130 (1): 1–7. doi:10.1007/s00432-003-0498-7. PMID 14564513.
  9. ↑ Ewer M, Yeh ET. Cancer and the Heart.1st ed. 2006; 2nd ed. 2013, 550p,People's Medical Publishing House,USA, 2013:ISBN 978-1607950400.
  10. ↑ Doroshow JH (August 2012). "Dexrazoxane for the prevention of cardiac toxicity and treatment of extravasation injury from the anthracycline antibiotics". Current Pharmaceutical Biotechnology. 13 (10): 1949–56. doi:10.2174/138920112802273245. PMID 22352729.
  11. ↑ Harake D, Franco VI, Henkel JM, Miller TL, Lipshultz SE (July 2012). "Cardiotoxicity in childhood cancer survivors: strategies for prevention and management". Future Cardiology. 8 (4): 647–70. doi:10.2217/fca.12.44. PMC 3870660Freely accessible. PMID 22871201.
  12. ↑ Carter S, Bakowski M, Hellmann K. Chemotherapy of Cancer.350P, Wiley,1977:ISBN 9780471029359.
  13. ↑ Cox R. Sir Stanford Cade, KBE CB. Ann R Coll Surg Engl. 1974 Feb;54(2):94-6.
  14. ↑ Steiner R, Hellmann K (April 2013). "Dexrazoxane prevention of anthracycline cardiomyopathy". Journal of Clinical Oncology. 31 (10): 1379. doi:10.1200/JCO.2012.46.9908. PMID 23439750.
  15. ↑ Hellmann K, Rhomberg W. "Razoxane and Dexrazoxane - Two Multifunctional Agents". 243p, Springer 2011: ISBN 978-90-481-9167-3;e-book: ISBN 978-90-481-9168-0.
  16. ↑ Eccles SA, Steiner RK (August 2012). "Kurt Hellmann D.M., D.Phil. Oxon. A happy 90th birthday!". Clinical & Experimental Metastasis. 29 (6): 523–6. doi:10.1007/s10585-012-9490-4. PMID 22695808.
  17. ↑ "Kurt HELLMAN Obituary: View Kurt HELLMAN's Obituary by The Times". Announcements.thetimes.co.uk. 2013-04-02. Retrieved 2013-05-22.
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