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Temporal Comparisons of Immune Status and Target Organ Histology in Mice Fed Carcinogenic 5-Nitrofurans and Their Nornitro Analogs¹

Don B. Headley, Roger G. Klopp², Preston M. Michie³, Erdoan Ertürk and George T. Bryan⁴

Division of Clinical Oncology, Department of Human Oncology, Wisconsin Clinical Cancer Center, Madison, Wisconsin 53792

Immune status and target organ histology were temporally evaluated in mice fed either carcinogenic 5-nitrofurans or their noncarcinogenic nornitro analogs. Mice were fed either the leukemogen N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide (NFTA) or the urinary bladder carcinogen N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide or their nornitro analogs, N-[4-(2-furyl)-2-thiazolyl]acetamide or N-[4-(2-furyl)-2-thiazolyl]formamide, at three dosage levels for a period of 12 weeks. The antibody-mediated immunity and cell-mediated immunity were evaluated via the Cunningham modification of the Jerne plaque method and cell-mediated lympholysis technique, respectively. NFTA-fed mice exhibited statistically significant and dose-dependent immunosuppression of antibody- and cell-mediated immunities. Antibody-mediated immunity responses at the high dose (1000 ppm) were 19, 19, 31, and 19% of control values at Weeks 4, 7, 10, and 13, respectively. Cell-mediated immunity responses were 29, 25, and 8% of control values at Weeks 7, 10, and 16, respectively (p 0.01). Mice fed N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide, N-[4-(2-furyl)-2-thiazolyl]acetamide, or N-[4-(2-furyl)-2-thiazolyl]formamide showed occasional depressions of immune responses. These responses were unsustained and appeared to be biologically anomalous when compared to responses of NFTA-fed mice. The immunosuppressed state of NFTA-fed mice was observed prior to the histological appearance of leukemia. Leukemia development in NFTA-fed mice was highly dose dependent with the latent period inversely proportional to NFTA dosage. Hyperplastic foci in the thymus, spleen, or lymph nodes were noted early in the feeding period. Leukemic involvement of these organs was observed at later times. Despite the short feeding time, N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide-fed mice surviving >18 weeks exhibited a urinary bladder hyperplasia (20 of 85), transitional cell carcinoma (2 of 85), and leukemia (30 of 85). The nornitro analogs, N-[4-(2-furyl)-2-thiazolyl]acetamide and N-[4-(2-furyl)-2-thiazolyl]formamide, failed to exhibit any statistically significant tumor incidences.

¹ Supported in part by Grants CA 10017, CA 11946, CA 14520, and CA 17449 from the National Cancer Institute, the latter grant through the National Bladder Cancer Project. Preliminary reports of this work have been made (14, 21).

² Present address: Department of Pediatrics, University of Wisconsin Center for Health Sciences, K4/443 CSC, 600 Highland Avenue, Madison, Wis. 53792.

³ Present address: 2525 SE 22, Portland, Oreg. 97202.

⁴ To whom requests for reprints should be addressed, at Department of Human Oncology, Wisconsin Clinical Cancer Center, University of Wisconsin Center for Health Sciences, K4/528 CSC, 600 Highland Avenue, Madison, Wis. 53792.

Received 6/18/79. Accepted 1/ 6/81.