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Evidence for a role of chloroethylaziridine in the cytotoxicity of cyclophosphamide.
- Source :
-
Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2000; Vol. 45 (4), pp. 335-44. - Publication Year :
- 2000
-
Abstract
- 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.<br />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.<br />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.<br />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.<br />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.
- Subjects :
- Acrolein chemistry
Antineoplastic Agents, Alkylating chemistry
Aziridines chemistry
Breast Neoplasms pathology
Cell Count drug effects
Cell Nucleus metabolism
Cell Survival drug effects
Cyclophosphamide analogs & derivatives
Cyclophosphamide chemistry
Humans
Indicators and Reagents
Kinetics
Magnetic Resonance Spectroscopy
Tumor Cells, Cultured
Antineoplastic Agents, Alkylating toxicity
Aziridines toxicity
Cyclophosphamide toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 0344-5704
- Volume :
- 45
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cancer chemotherapy and pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 10755323
- Full Text :
- https://doi.org/10.1007/s002800050049