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Molecular Pharmacology of Nitrosoureas

  • K. D. Tew
  • M. E. Smulson
  • P. S. Schein
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 76)

Abstract

The development of a wide range of aliphatic nitrosamides has followed the original observation that l-methyl-l-nitroso-3-nitrosoguanidine had reproducible antitumor activity against murine L1210 leukemia [7]. The resultant synthesis of new N-nitroso containing compounds has produced two general classes of drug, the methyl and chloroethyl nitrosoureas. Both groups of drugs have the potential to alkylate and carbamoylate cellular macromolecules under physiologic conditions with no prelim- inary enzymatic activation required. In addition, the original observation that 1-methyl-1-nitrosourea (MNU) increased the life span of mice bearing intercranially implanted L1210 cells [25] was correlated with the lipid solubility of the drug and its potential to cross the blood brain barrier. This property instigated the development and clinical use of a series of chloroethyl nitrosoureas, including, l,3-bis(2-chloroethyl)-l-nitrosourea (BCNU) [11], l-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU) and eventually methyl-CCNU. These drugs have established clinical antitumor activity for a broad range of human malignancies including acute lymphocytic leukemia, lymphomas, myeloma, melanoma, gliomas, and gastrointestinal neoplasms [32]. Unfortunately, these same agents produce delayed and cumulative bone marrow toxicity which is a serious limitation to their therapeutic efficacy. The attachment of MNU to the C-2 position of glucose (streptozotocin) greatly reduced this myelosuppression and further led to the synthesis of a chloroethyl derivative, 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose or chlorozotocin [12] which, similarly exhibited minimal myelotoxicity [24].

Keywords

Murine Bone Marrow Molecular Pharmacology Micrococcal Nuclease Nonhistone Protein Murine Bone Marrow Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer-Verlag Berlin Heidelberg 1981

Authors and Affiliations

  • K. D. Tew
    • 1
  • M. E. Smulson
    • 1
  • P. S. Schein
    • 1
  1. 1.Georgetown University Medical CenterN.W.USA

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