Comparative immunotoxicity assessment of N4-Trimethoxybenzoyl-5'-deoxy-5- fluorocytidine (Ro 09-1390) and 5'-deoxy-5-fluorouridine (5'-DFUR) in BDF1 mice.
N4-Trimethoxybenzoyl-5'-deoxy-5-fluorocytidine (Ro 09-1390) and 5'-deoxy-5-fluorouridine (5'-DFUR) are 5-fluorouracil (5-FU) derivatives developed as anti-tumor pharmaceuticals. To evaluate immunotoxicities of these compounds, BDF1 mice were administered vehicle, 300-2700 mg (0.68-6.14 mmol)/kg/day of Ro 09-1390, or 100-900 mg (0.41-3.66 mmol)/kg/day of 5'-DFUR for 1 to 7 days, and effects on cellularity in lymphoid organs were assessed by immunohistochemistry as well as general toxicologic parameters. To distinguish compound-specific direct action from nonspecific indirect action caused by dietary reduction, dietary restriction groups were also included as control groups. Final body weight, thymus weight, bone marrow cell number (BMC), and leukocyte number were reduced with high dose of both compounds. Reduction of BMC in groups administered with Ro 09-1390 or 5'-DFUR was more severe than in dietary restriction groups given comparative amount of diet with compound-administered groups. Diffuse thymic cortical hypoplasia was observed in the highest dose of both compounds and more apparent in the Ro 09-1390 than in the 5'-DFUR. Focal nodular thymocyte hyperplasia was observed especially in the lower dose of 5'-DFUR. The results indicate that immunotoxic profiles of Ro 09-1390 and 5'-DFUR are very similar and characterized primarily by myelotoxicity and Ro 09-1390 is approximately two-times less toxic than 5'-DFUR on a molar basis in BDF1 mice.
Inoue
T
T
Department of Toxicology and Pathology, Nippon Roche Research Center, Kanagawa, Japan.
Anderson
T D
TD
Hayes
T J
TJ
Horii
I
I
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects*; D003345:Corticosterone / Q000097:blood; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005467:Floxuridine / Q000633:toxicity*; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007536:Isomerism; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D017701:Reticulocyte Count / Q000187:drug effects; D013950:Thymus Gland / Q000473:pathology*
D007166:Immunosuppressive Agents; D005467:Floxuridine; D003841:Deoxycytidine; C063993:Ro 09-1390; C025034:doxifluridine; D003345:Corticosterone