Article ID: CBB089015962

Chemistry, Cyclophosphamide, Cancer Chemotherapy, and Serendipity: Sixty Years On (2021)

unapi

The year 2019 marked the 60th anniversary of the approval of cyclophosphamide (CP) as an anticancer drug by the U.S. Food & Drug Administration in 1959 for the treatment of lymphoma. Between 1959 and 2019 there were ~50,000 publications listed in PubMed that have CP in the title and/or abstract, with these annual numbers showing a continual increase, and over 1,800 such articles in 2019 alone. The discovery of CP is a prime example of serendipity in science, which also applies to key elements of the metabolism and pharmacological basis for the specificity of the cytotoxicity of CP toward cancer cells. Phosphoramide mustard, the principal metabolite of CP with DNA alkylating activity, was synthesized and reported by Friedman and Seligman in 1954 prior to the discovery of CP. Interestingly, the original drug design premise for synthesizing PM, which was based on elevated phosphamidase enzyme activity in cancer cells proved to be incorrect. While this wrong premise also led to the synthesis of CP, as a six-membered ring cyclic phosphamidase-activated precursor of PM, the actual metabolic conversion of CP to PM was subsequently found to involve a surprisingly complex array of metabolites and metabolic pathways, all completely unrelated to phosphamidase. Although the molecular structure of CP has an asymmetrically substituted, i.e. chiral phosphorus center, the racemic mixture of the Rp and Sp enantiomers of CP was used throughout its initial investigations and subsequent clinical trials despite the involvement of an initial enzyme-mediated metabolic activation step, which could, in principle, be stereoselective for only one of the enantiomers of CP. Stereochemical investigations along those lines were eventually carried out, but the results did not warrant replacement of racemic CP with either enantiomer in the clinic. Amazingly, there are now ~4,000 structural congeners of PM listed in Chemical Abstracts, but none have led to an anticancer drug superior to CP. This account provides a synopsis of the key chemistry and stereochemistry investigations that comprise this story of CP, as a remarkable instance of serendipity in science, and my chance involvement in the unfolding of this fascinating story.

...More
Citation URI
https://data.isiscb.org/isis/citation/CBB089015962/

Similar Citations

Article Jack S. Cohen; (2021)
History of Research on Antisense Oligonucleotide Analogs (/isis/citation/CBB450691525/)

Article Manuela Rizzi; Matteo Gallazzi; Francesca Tosetti; Lorenzo Mortara; (2020)
The tumor-endothelium cell interaction in pioneering studies and the revisited concept on the angiogenesis process during tumor progression and metastasis (/isis/citation/CBB704955825/)

Article Giulia Bovone; (2019)
L’Arsenico: da strumento di morte ad antitumorale (XIX – XX - XXI secolo) (/isis/citation/CBB158105733/)

Chapter Roberto Taramelli; (2016)
Una nuova visione del cancro attraverso le lenti della dinamica dei sistemi (/isis/citation/CBB225293248/)

Article Kauffman, George B.; Adloff, Jean-Pierre; (2013)
The Centenary of the Maillard Reaction (/isis/citation/CBB001211975/)

Article Marc Henry; (2021)
Thermodynamics of Life (/isis/citation/CBB851479700/)

Article Pittard, A. J.; Cox, G. B.; (2010)
Frank William Ernest Gibson 1923--2008 (/isis/citation/CBB001022179/)

Article Maria Benedetta Gambacorti-Passerini; Lucia Zannini; (2017)
La "cura": tra dimensioni terapeutiche, esistenziali ed educative (/isis/citation/CBB648796466/)

Article Rossella Costa; (2017)
From Chemical to Genetic Individuality. Evolving Concepts and Therapeutic Approaches (/isis/citation/CBB900408942/)

Article Mauro Capocci; (2017)
Regimen Strikes Back. Diagnosis, Genes and the Patient (/isis/citation/CBB699749755/)

Article Junardi Harahap; Rita Destiwati; (2023)
"Hijrah Medicine": a study of the transition of medicine from general to Islamic-based medicine in Indonesia (/isis/citation/CBB493281004/)

Article Sharma, Padmanee; Allison, James P.; (2012)
Lloyd J. Old (1933--2011) (/isis/citation/CBB001320473/)

Book Cornwall, Claudia; (2013)
Catching Cancer: The Quest for Its Viral and Bacterial Causes (/isis/citation/CBB001213235/)

Article Natasa Kustrimovic; Daniela Gallo; Andrea De Lerna Barbaro; Eliana Piantanida; Lorenzo Mortara; Maria Laura Tanda; (2023)
The discovery of TNF-alpha: A historical perspective (/isis/citation/CBB446223292/)

Article Harriet L. Crosby; (2016)
Jane Cooke Wright (1919–2013): Pioneering Oncologist, Woman and Humanitarian (/isis/citation/CBB951031731/)

Article Neeraja Sankaran; Ton van Helvoort; (2016)
Andrewes's Christmas Fairy Tale: Atypical Thinking About Cancer Aetiology in 1935 (/isis/citation/CBB089322763/)

Book Gregory J. Morgan; (2022)
Cancer Virus Hunters: A History of Tumor Virology (/isis/citation/CBB284978916/)

Authors & Contributors
Mortara, Lorenzo
Cohen, Jack S.
Gallazzi, Matteo
Eliana Piantanida
Henry, Marc
Tosetti, Francesca
Concepts
Medicine
Oncology
Cancer; tumors
Therapeutics
Biochemistry
Chemistry
Time Periods
20th century
21st century
20th century, late
19th century
17th century
Places
United States
Indonesia
Netherlands
Australia
Comments

Be the first to comment!

{{ comment.created_by.username }} on {{ comment.created_on | date:'medium' }}

Log in or register to comment