This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, P. Articles by Povirk, L. F. Search for Related Content PubMed PubMed Citation Articles by Wang, P. Articles by Povirk, L. F.

Melphalan-induced Mutagenesis in an SV40-based Shuttle Vector: Predominance of A · TT · A Transversions¹

Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298

The base and sequence specificity of mutagenesis by the carcinogenic antitumor agent melphalan (L-phenylalanine mustard) was examined by in vitro treatment of the plasmid pZ189 followed by replication in human 293 cells, rescue in bacteria, and sequence analysis of mutations in the supF gene. Melphalan was strongly mutagenic in this assay. The induced mutations were predominantly base substitutions, with a minor component of small deletions (3–80 base pairs). Surprisingly, A · TT · A transversions were by far the most frequent substitutions, suggesting that modifications of adenine may play a major role in mutagenesis. More than half the substitutions were clustered in a C-T-A-A sequence in the anticodon loop. No base substitutions were detected at G-N-C sequences, which are thought to be potential sites of DNA interstrand cross-links. The results raise the possibility that the cytotoxic and mutagenic effects of melphalan may be separable.

¹ Supported by Grant CA40615 from the National Cancer Institute, DHHS.

² Supported in part by a fellowship from the Carol Jean Lipman MacFarlane and Ann Debra Lipman Fund.

³ Supported by Training Grant ES07087 from the National Institute of Environmental Health Sciences, DHHS.

⁴ To whom requests for reprints should be addressed, at P.O. Box 230, Medical College of Virginia, Richmond, VA 23298.

Received 3/19/90. Accepted 8/30/90.

This article has been cited by other articles:

				L. J. Niedernhofer, J. S. Daniels, C. A. Rouzer, R. E. Greene, and L. J. Marnett Malondialdehyde, a Product of Lipid Peroxidation, Is Mutagenic in Human Cells J. Biol. Chem., August 15, 2003; 278(33): 31426 - 31433. [Abstract] [Full Text] [PDF]

				A. Inga, F.-X. Chen, P. Monti, A. Aprile, P. Campomenosi, P. Menichini, L. Ottaggio, S. Viaggi, A. Abbondandolo, B. Gold, et al. N-(2-Chloroethyl)-N-nitrosourea Tethered to Lexitropsin Induces Minor Groove Lesions at the p53 cDNA That Are More Cytotoxic than Mutagenic Cancer Res., February 1, 1999; 59(3): 689 - 695. [Abstract] [Full Text] [PDF]

				X.-Y. Gu, R. A.O. Bennett, and L. F. Povirk End-joining of Free Radical-mediated DNA Double-strand Breaks in Vitro Is Blocked by the Kinase Inhibitor Wortmannin at a Step Preceding Removal of Damaged 3' Termini J. Biol. Chem., August 16, 1996; 271(33): 19660 - 19663. [Abstract] [Full Text] [PDF]