Effects of enantiomeric homogeneity on the in vitro metabolism and in vivo anticancer activity of (+)- and (−)-cyclophosphamide

Tsui, Fai-Po; Brandt, Joan A.; Zon, Gerald

doi:10.1016/0006-2952(79)90100-x

Cited by 14 publications

(1 citation statement)

References 26 publications

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“…Collectively, these various experimental results suggested to us that "there is an unusually low degree of biological stereoselectivity associated with the metabolism of CP enantiomers." 48 Stec's laboratory carried out far more comparative experiments of this sort in vitro and in vivo in several animal species, namely, mouse, rabbit, and rat, in collaboration with investigators at the Institute of Cancer Research, Surrey, England, as summarized in the introductory section of a 1979 publication (Jarman et al 49 ) that extended these collaborative studies to humans. The protocol for this small pilot study 49 involved 4 patients with carcinoma of the lung who had normal renal and hepatic function as measured by standard biochemical tests, and none had received CP previously.…”

Section: Effects Of Stereochemistry On Cp Metabolism In Humansmentioning

confidence: 99%

Chemistry, Cyclophosphamide, Cancer Chemotherapy, and Serendipity: Sixty Years On

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2021

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Cambridge Dictionary: serendipity | noun | the phenomenon of finding interesting or valuable things by chance. The year 2019 marked the 60th anniversary of the approval of cyclophosphamide (CP) as an anticancer 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 (PM), HO(H2N)P(O)N(CH2CH2Cl)2, 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 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.

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Section: Effects Of Stereochemistry On Cp Metabolism In Humansmentioning

confidence: 99%