~ Dr. Dennis Morgan
Every oncologist who treats patients has at one time or another used a derivative of a chemical warfare agent to get the job done. The serendipitous arc of history that lead from sulfur mustard to nitrogen mustard to bendamustine traces a story of scientific discovery modulated by the best and worst of human intentions.
In an era when chemotherapy is all about proteomics, genomics and high-roller economics, the popularity of Bendamustine represents a comeback for the lowly alkylating agent. The battlefields of WWI Europe contain the story of its distant origin.
Lommel and Steinkopf developed bis(2-chloroethyl) sulfide. It smelled like mustard, therefore was commonly known as sulfur mustard, or LOST (LOmmel/STeinkopf) to the German military, who commissioned it in the laboratory of the Nobel laureate Fritz Haber. Haber’s great achievement was industrial synthesis of ammonia (many lives were saved with abundant fertilizer, and lost from abundant explosives). Mustard gas blisters skin and lungs causing disfigurement and death. It remains a Chemical Weapons Convention Schedule I Toxic Chemical, along with Sarin gas, Ricin, and its cousin Nitrogen mustard.
As a weapon, Nitrogen Mustard is code named HN2. Its chemical name, Bis(2-chloroethyl)(methyl)amine, reveals it’s similarity to mustard gas. In medicine it is known as mechlorethamine, part of the MOPP regimen for Hodgkin’s Disease. Transformation from weapon to drug also involved government sponsored research. Only this time it’s the US Army in WWII.
Dr. Stewart Alexander first observed myelo-suppression from mustard gas, in people exposed to it after a German air raid. The SS John Harvey was blown up, spewing its American cargo of 130,000 pounds of liquid sulfur mustard over the town of Bari, Italy. After the war, the Dean of the Yale Medical School won a secret government contract to study chemical warfare.
He chose two assistant professors for this task—Goodman and Gilman, (yes, the ones who later wrote your (the) textbook of pharmacology). They worked out an antidote (thiosulate) but more importantly made a more stable chemical by substituting nitrogen for sulfur. This agent “X”shrank lymph nodes and caused leukopenia in rabbits. They persuaded a a chest surgeon to provide the first patient ever to be treated with IV chemotherapy. In 2011 the records of “JD” resurfaced from the files of Yale’s Pathology Department. A 47 year old Polish immigrant working at a ball-bearing factory in Connecticut had lymphosarcoma. On Aug 27, 1942 he received the ‘synthetic lymphocidal chemical.’ The first cycle yielded great improvement. The second and third met with resistance and he died after three months in the hospital. But the proof of concept was now established.
MOPP was a game changer in oncology. DeVita pioneered its use at the NCI in the 1960s. It could overcome the resistance seen with nitrogen mustard alone and was a beacon of hope for Hodgkin’s patients in particular, and the concept of chemotherapy in general. The “M” in MOPP is of course for Mustargen (mechlorethamine, mustine, or nitrogen mustard).
Mustargen eventually spawned Estramustine (when attached to estradiol) for prostate cancer, and Bendamustine, which has replaced nitrogen mustard on the WHO Model List of 40 essential cytotoxic drugs.
Bendamustine was available only in East Germany until the fall of the Berlin Wall in 1990. It was synthesized almost three decades earlier by Ozegowski and Krebs (no, not that Krebs). They added a benzimidole ring to the hallmark chloroethylamine group that is common to alkylating agents. This resulted in curious new properties: more potent cross-linking of DNA, non-cross resistance to other alkylators, purine analog similarity, a broad spectrum of tumor activity and synergy with rituxin. Cephalon won FDA approval in 2008 as Treanda, which is rapidly expanding its role in lymphoid neoplasms especially.
The initial success of alkylating agents in treating lymphoid malignancies set the stage for all that followed in chemotherapy. But not without missteps along the way. I recall one evening when I was a fellow, sitting alone with Emil Frei as he reviewed his slides before presenting his talk to our group on the STAMP protocol. This used three alkylating agents, necessitating bone marrow rescue. I mused that it seemed quite toxic. His look of rebuke was stern and silent. Experimentation in chemotherapy is not for the faint of heart, apparently.
Do you think other traditional agents deserve re-evaluation for useful derivatives?
Dennis Morgan, MD is Assistant Clinical Professor University of Connecticut Health Center, Emeritus Staff Johnson Memorial Hospital and Medical Center Stafford CT and Past President Connecticut Oncology Association as well as Past Medical Director Phoenix Community Cancer Center, Enfield CT
Pioneers in chemotherapy
By Judith Schiff | May/Jun 2011
Pioneers in chemotherapy | Old Yale | Yale Alumni Magazine https://yalealumnimagazine.com/articles/3173-pioneers-in-chemotherapy
The initial clinical trial of nitrogen mustard. Gilman, Alfred. The American Journal of Surgery , Vol 105 , Issue 5 , 574 – 578. http://www.americanjournalofsurgery.com/article/0002-9610(63)90232-0/abstract
Bendamustine: Rescue of an Effective Antineoplastic Agent From the Mid-Twentieth Century. Lorenzo M. Seminars in Hematology. Apr 2011. Vol 48, Supp. 1, pp S4–S11. http://www.seminhematol.org/article/S0037-1963(11)00024-2/fulltext
The Evolving Role of Bendamustine in Lymphoid Malignancy: Understanding the Drug and Its Mechanism of Action. Lorenzo M. Leoni, Ed. Seminars in Hematology. Apr 2011. Vol 48, Supp 1, S1-S38. http://www.seminhematol.org/issue/S0037-1963(11)X0003-3
Bendamustine: Rebirth of an Old Drug. Cheson Bruce D. and Rummel Mathias J. J Clin Oncol 27:1492-1501. http://williams.medicine.wisc.edu/bendamustine_2009.pdf
WHO Model List of Essential Medicines, Wikipedia. https://en.wikipedia.org/wiki/WHO_Model_List_of_Essential_Medicines#Cytotoxic_and_adjuvant_medicines
Wikipedia articles on: history of chemotherapy, alkylating agents, chemical weapons convention, Wilhelm Steinkopf, Fritz Haber, Goodman and Gilman, sulfur mustard, nitrogen mustard, bendamustine, MOPP, estramustine.