title: Dose-response relationships of cytotoxicity, PFC response and histology in the spleen in rats treated with alkylating agents.
abstract: Our previous study revealed the appropriate conditions for the plaque- forming cell (PFC) assay in rats. Using this assay in the present study, dose-response relationships of cytotoxicity, PFC response and histology in the spleen were evaluated in rats receiving alkylating agents. Rats were given a single intravenous administration of cyclophosphamide (CY) at a dose of 3, 10 or 30 mg/kg. Spleen weights and cellularity were decreased in the rats treated with 30 mg/kg. Suppressed PFC response wes observed in the rats receiving 10 mg/kg or more. In the rats treated with CY at 1, 3 or 10 mg/kg for 7 days, spleen weights and cellularity and PFC response were reduced at doses of 3 mg/kg or more. Treatment with the other alkylating agents, however, had a different consequence. Namely, in the rats treated with nitromin once or for 7 days, spleen weights and cellularity were decreased at a dose lower than that causing a reduction in the PFC response. In the rats treated with melphalan or chlorambucil, the weights and cellularity of the spleen tended to be decreased at a dose lower than that suppressing the PFC response. Histologically, in the case of CY, the marginal zone was narrow with cellular depletion in the rates receiving 3 mg/kg, whereas little change was seen in the periarteriolar lymphoid sheath (PALS). At a dose of 10 mg/kg, the marginal zone was markedly atrophied and slight atrophy of the PALS was seen. On the other hand, in the rats treated with nitromin, a dose-related decrease in the size of the spleen was seen without changes in the tissue architecture. Melphalan caused atrophy of both the marginal zone and the PALS at a dose suppressing PFC response. Regarding the red pulp, the extramedullary hematopoiesis disappeared with melphalan and nitromin, but not with CY. These results indicate that the decreases in weights and cellularity and histological changes in the spleen caused by the alkylating agents are detectable at the dose suppressing PFC response except for CY, which has a marked immunosuppressive action. Furthermore, the observed histological findings in the spleen were characteristic of each alkylating agent.
authors.affiliation: Drug Safety Research Laboratories, Takeda Chemical Industries, Ltd. Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Doi
authors.forename: H
authors.initials: H
authors.lastname: Nagai
authors.forename: R
authors.initials: R
authors.lastname: Tsukuda
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D002452:Cell Count / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002699:Chlorambucil / Q000633:toxicity; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006462:Hemolytic Plaque Technique; D007107:Immune System / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D008466:Mechlorethamine / Q000633:toxicity; D008558:Melphalan / Q000633:toxicity; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D012680:Sensitivity and Specificity; D013154:Spleen / Q000166:cytology / Q000187:drug effects* / Q000276:immunology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002699:Chlorambucil; D008466:Mechlorethamine; D003520:Cyclophosphamide; D008558:Melphalan