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Evidence for a role of chloroethylaziridine in the cytotoxicity of cyclophosphamide.

Publication ,  Journal Article
Flowers, JL; Ludeman, SM; Gamcsik, MP; Colvin, OM; Shao, KL; Boal, JH; Springer, JB; Adams, DJ
Published in: Cancer Chemother Pharmacol
2000

UNLABELLED: A number of investigators have observed that the use of 4-hydroperoxycyclophosphamide (4-HC) in multiwell plate cytotoxicity assays can be associated with toxicity to cells in wells that contain no drug. Previous reports have implicated diffusion of 4-HC decomposition products, and acrolein in particular, as the active species. PURPOSE: The purpose of this study was to elucidate the species responsible for the airborne cytotoxicity of 4-HC, and to devise ways to minimize such effects in chemosensitivity assays. METHODS: To this end, analogues of 4-HC were synthesized to identify the contributions of individual cyclophosphamide metabolites to cytotoxicity. The analogues were then tested for activity against three human breast tumor cell lines (including a line resistant to 4-HC), and one non-small-cell lung carcinoma line. Cytotoxicity was evaluated by assays that quantitate cellular metabolism and nucleic acid content. RESULTS: Didechloro-4-hydroperoxycyclophosphamide, a compound that generates acrolein and a nontoxic analogue of phosphoramide mustard, gave no cross-well toxicity. In contrast, a significant neighboring well effect was observed with phenylketophosphamide, a compound that generates phosphoramide mustard but not acrolein. Addition of authentic chloroethylaziridine reproduced the airborne toxicity patterns generated by 4-HC and phenylketophosphamide. Increasing the buffering capacity of the growth medium and sealing the microtiter plates prevented airborne cytotoxicity. CONCLUSION: Since it is unlikely that phosphoramide mustard is volatile, these findings implicate chloroethylaziridine rather than acrolein as the volatile metabolite of 4-HC that is responsible for airborne cytotoxicity. The fact that chloroethylaziridine is generated in amounts sufficient to volatilize, diffuse across wells and cause cytotoxicity indicates that it is an important component in the overall cytotoxicity of 4-HC in vitro. Furthermore, these findings suggest that chloroethylaziridine may also contribute to the toxicity of cyclophosphamide in vivo.

Duke Scholars

Published In

Cancer Chemother Pharmacol

DOI

ISSN

0344-5704

Publication Date

2000

Volume

45

Issue

4

Start / End Page

335 / 344

Location

Germany

Related Subject Headings

  • Tumor Cells, Cultured
  • Oncology & Carcinogenesis
  • Magnetic Resonance Spectroscopy
  • Kinetics
  • Indicators and Reagents
  • Humans
  • Cyclophosphamide
  • Cell Survival
  • Cell Nucleus
  • Cell Count
 

Citation

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Flowers, J. L., Ludeman, S. M., Gamcsik, M. P., Colvin, O. M., Shao, K. L., Boal, J. H., … Adams, D. J. (2000). Evidence for a role of chloroethylaziridine in the cytotoxicity of cyclophosphamide. Cancer Chemother Pharmacol, 45(4), 335–344. https://doi.org/10.1007/s002800050049
Flowers, J. L., S. M. Ludeman, M. P. Gamcsik, O. M. Colvin, K. L. Shao, J. H. Boal, J. B. Springer, and D. J. Adams. “Evidence for a role of chloroethylaziridine in the cytotoxicity of cyclophosphamide.Cancer Chemother Pharmacol 45, no. 4 (2000): 335–44. https://doi.org/10.1007/s002800050049.
Flowers JL, Ludeman SM, Gamcsik MP, Colvin OM, Shao KL, Boal JH, et al. Evidence for a role of chloroethylaziridine in the cytotoxicity of cyclophosphamide. Cancer Chemother Pharmacol. 2000;45(4):335–44.
Flowers, J. L., et al. “Evidence for a role of chloroethylaziridine in the cytotoxicity of cyclophosphamide.Cancer Chemother Pharmacol, vol. 45, no. 4, 2000, pp. 335–44. Pubmed, doi:10.1007/s002800050049.
Flowers JL, Ludeman SM, Gamcsik MP, Colvin OM, Shao KL, Boal JH, Springer JB, Adams DJ. Evidence for a role of chloroethylaziridine in the cytotoxicity of cyclophosphamide. Cancer Chemother Pharmacol. 2000;45(4):335–344.
Journal cover image

Published In

Cancer Chemother Pharmacol

DOI

ISSN

0344-5704

Publication Date

2000

Volume

45

Issue

4

Start / End Page

335 / 344

Location

Germany

Related Subject Headings

  • Tumor Cells, Cultured
  • Oncology & Carcinogenesis
  • Magnetic Resonance Spectroscopy
  • Kinetics
  • Indicators and Reagents
  • Humans
  • Cyclophosphamide
  • Cell Survival
  • Cell Nucleus
  • Cell Count