Summary
This study compares the two oxazaphosphorine compounds ASTA Z 7557 (AZ) and cyclophosphamide (CP) in their therapeutic activity as well as in their myelotoxicity and DNA damage being induced after a single intraperitoneal injection. Therapeutic activity was determined towards methylnitrosourea-induced rat mammary carcinomas in vivo and in vitro, resulting in comparable efficacy of both compounds at their optimal doses, respectively, with the sensitivity of individual tumors being reflected by the degree of inhibition of 3H-thymidine uptake of these cells in vitro.
Myelotoxicity was measured as inhibition of pluripotent (CFU-S) and macrophage-granulocyte committed (CFU-C) stem cells together with the extent of single strand breaks and DNA-DNA interstrand crosslinks in murine bone marrow. At equimolar base AZ was found to induce a higher level of DNA damage than CP in the bone marrow of mice 16 hours after a single intraperitoneal injection. Both compounds depressed the pluripotent stem cell compartment of the bone marrow to a similar extent, whereas AZ was significantly less toxic to the granulocyte cell lineage.
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Abbreviations
- AZ:
-
ASTA Z 7557; 2-[N,N,bis-(2-chloroethyl)-amino]-4-(2-sulphonato-ethylthio)-tetrahydro-2H-1,3,2, oxazaphosphorine-2-oxide
- CP:
-
Cyclophosphamide; 2-[N,N,bis-(2-chloroethyl)-amino]-1,3,2-oxazaphosporine-2-oxide
- CFU-C:
-
Granulocyte-committed stem cells
- CFU-S:
-
Pluripotent stem cells
- BCNU:
-
1,3-bis(2-chloroethyl)-1-nitrosourea
- MNU:
-
N-methyl-N-nitrosourea
- Mesna:
-
2-mercaptoethanesulphonate
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Berger, M.R., Bedford, P., Zeller, W.J. et al. A comparative study of therapeutic activity, myelotoxicity and DNA damage in the bone marrow of mice after cyclophosphamide and ASTA Z 7557 (INN mafosfamide). Invest New Drugs 2, 181–186 (1984). https://doi.org/10.1007/BF00232349
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DOI: https://doi.org/10.1007/BF00232349