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Induction of Thymic Lymphomas and Squamous Cell Carcinomas following Topical Application of Isopropyl Methanesulfonate to Female Hsd:(ICR)BR Mice¹

Departments of Environmental Medicine [A. S., S. M.] and Pathology [I. S.], New York University School of Medicine, New York, New York 10016

The goal of these experiments in female Hsd:(ICR)Br mice was to determine whether the direct-acting S_N1 alkylating carcinogen isopropyl methanesulfonate (IMS) is carcinogenic and to compare its effects with those of the direct-acting S_N2 methyl homologue, methyl methanesulfonate (MMS). The compounds were administered by topical application and s.c. injection. Analysis at the 288th day of mice receiving s.c. injections of IMS and MMS was the subject of a previous report (A. Segal et al., Proc. Soc. Exp. Biol. Med., 183: 132–135, 1986). The s.c. and topical application experiments were terminated at the 450th day and the final results are reported in this paper. In mice treated by s.c. injection with IMS, thymic lymphomas were observed in at least 20 of 32 mice, the first at the 40th day, and neoplasms were not observed at the injection site. Of the 30 MMS-treated mice, 11 developed sarcomas at the injection site and one thymic lymphoma was observed. In mice treated topically with IMS, thymic lymphomas were observed in 20 of 30 treated mice, the first at the 102nd day, and squamous cell carcinomas at the injection site were observed in 9 mice. Neither squamous cell carcinomas nor thymic lymphomas were observed in 30 mice following topical application of MMS. The direct-acting S_N2 aklyating carcinogen ß-propiolactone was also administered by topical application. At the 450th day, at the same dose used for MMS (40 µmol/application), papillomas of the skin were observed in 25 of 30 treated mice, squamous cell carcinomas of the skin were seen in 17 mice, and one thymic lymphoma was observed. The results suggest that the rapid induction of thymomas by IMS may be related to its ability to alkylate exocyclic oxygen atoms in DNA of hemopoietic cells and also to a sensitivity of these cells to such lesions.

¹ This research was supported by Grants ES 00260 and ES 03563 from the National Institute of Environmental Health Sciences, Grants CA 24124 and CA 13343 from the National Cancer Institute, and Special Institutional Grant 00009 from the American Cancer Society.

² To whom requests for reprints should be addressed, at Department of Environmental Medicine, New York University Medical Center, 550 First Avenue, New York, NY 10016.

Received 12/29/86. Revised 3/30/87. Accepted 4/ 6/87.