Cyclophosphamide and cancer: golden anniversary

Abstract

Cyclophosphamide remains one of the most successful and widely utilized antineoplastic drugs. Moreover, it is also a potent immunosuppressive agent and the most commonly used drug in blood and marrow transplantation (BMT). It was initially synthesized to selectively target cancer cells, although the hypothesized mechanism of tumor specificity (activation by cancer cell phosphamidases) transpired to be irrelevant to its activity. Nevertheless, cyclophosphamide's unique metabolism and inactivation by aldehyde dehydrogenase is responsible for its distinct cytotoxic properties. Differential cellular expression of aldehyde dehydrogenase has an effect on the anticancer therapeutic index and immunosuppressive properties of cyclophosphamide. This Review highlights the chemistry, pharmacology, clinical toxic effects and current clinical applications of cyclophosphamide in cancer and autoimmune disorders. We also discuss the development of high-dose cyclophosphamide for BMT and the treatment of autoimmune diseases.

Key Points

  • Cyclophosphamide is an inactive prodrug that requires enzymatic and chemical activation; the resultant nitrogen mustard produces the interstrand and intrastrand DNA crosslinks that account for its cytotoxic properties

  • The major mechanism of cyclophosphamide detoxification involves aldehyde dehydrogenase; cells with high proliferative potential express high levels of aldehyde dehydrogenase and as a consequence are relatively resistant to cyclophosphamide

  • Cyclophosphamide, in combination with other antineoplastic agents, is used for the treatment of various cancers, including breast, lymphoid and pediatric malignancies

  • Cyclophosphamide is also widely used in bone marrow transplantation 'conditioning' and 'mobilization' regimens, and for the treatment of different autoimmune conditions

  • The toxic effects of cyclophosphamide include bone marrow suppression, cardiac and gonadal toxicity, hemorrhagic cystitis and carcinogenesis, with cumulative dose being the principal risk factor

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Figure 1: Formation of aziridinium ion from nitrogen mustard and its DNA alkylating activity.
Figure 2: The metabolic pathway of cyclophosphamide.
Figure 3: Differential sensitivities between hematopoietic stem cells and lymphocytes to cyclophosphamide's cytotoxic effect.

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Acknowledgements

The authors thank Dr. M. J. Higgins for her helpful discussion about the breast cancer section.

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Correspondence to Ashkan Emadi.

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Competing interests

Under a licensing agreement between Accentia Pharmaceuticals and the Johns Hopkins University, R. A. Brodsky and R. J. Jones are entitled to share royalty received by the University on sales of a method of administering high-dose cyclophosphamide. The study described in this article could impact the value of this method of administering the drug. The terms of this agreement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies. A. Emadi declares no competing interests.

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Emadi, A., Jones, R. & Brodsky, R. Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol 6, 638–647 (2009). https://doi.org/10.1038/nrclinonc.2009.146

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