This Article Full Text (PDF) References Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Saved Citations Download to citation manager Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Doi, T. Articles by Suzuki, T. Search for Related Content PubMed Articles by Doi, T. Articles by Suzuki, T. Social Bookmarking                         What's this?

Dose–Response Relationships of Weight, Cellularity, Plaque-Forming Cell Response, and Histology in the Spleen of Rats Treated with Antimetabolites

Drug Safety Research Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan

Hirofumi Nagai

Drug Safety Research Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan

Ryoichi Tsukuda

Drug Safety Research Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan

Tsuyoshi Suzuki

Drug Safety Research Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan

Our previous reports revealed the usefulness of investigating the changes in the weight, cellularity, and histology in the spleen caused by alkylating agents to evaluate immunotoxicity, compared with the plaque-forming cell (PFC) assay using appropriate conditions. In this study, dose–response relationships of weight, cellularity, PFC response, and histology in the spleen in rats treated with antimetabolites were studied. A single administration of azathioprine or 6-mercaptopurine (6-MP) caused decreases in spleen weights and cellularity and the PFC response at nearly the same dose level. In the rats treated with these agents for 7 days, spleen weights and cellularity tended to be decreased at doses lower than those suppressing the PFC response. In the rats singly treated with 5-fluorouracil (5-FU), spleen weights and cellularity were decreased at a dose lower than that suppressing the PFC response. At low and middle doses, the PFC response was inversely enhanced by this agent. A 7-day administration of 5-FU caused reductions in spleen weights and cellularity and PFC response at the same dose level. In addition, the spleen in the rats dosed with azathioprine, 6-MP, or 5-FU was histopathologically examined and indicated a dose-related decrease in the size of the spleen without changes in the tissue architecture at doses suppressing the PFC response. On the other hand, in the red pulp, the extramedullary hematopoiesis disappeared by these antimetabolites at the doses. These results indicate that decreases in the weight and cellularity and histological changes in the spleen caused by antimetabolites are detectable at doses suppressing the PFC response.

Key Words: Immunotoxicity • Fischer 344 rats • Spleen • Azathioprine • 6-Mercaptopurine • 5-Fluorouracil.

International Journal of Toxicology, Vol. 15, No. 5, 394-407 (1996)
DOI: 10.3109/10915819609018006


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?