Influence of cyclophosphamide and other immunosuppressive drugs on immune disorders and neoplasia in NZB/NZW MICE

Hahn, Bevra H.; Knotts, Linda L.; Ng, Mary Pei Ern; Hamilton, Tom R.

doi:10.1002/art.1780180212

Cited by 77 publications

(26 citation statements)

References 13 publications

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“…Neoplasms arose in 100% of treated females, compared to tumor incidence of 6% in control female mice (4). The increased incidence of neoplasms in cyclophosphamide-treated mice was confirmed by other investigators (12,13). Untreated NZB/NZW mice have a low background incidence of malignancy (43).…”

Section: Therapy Lesionssupporting

confidence: 69%

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Accelerated appearance of neoplasms in female nzb/nzw mice treated with high‐dose cyclophosphamide

Walker

Anver

1979

Arthritis & Rheumatism

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Prolonged immunosuppressive therapy with cyclophosphamide increases the prevalence of neoplasms in NZB/NZW mice, an animal model of systemic lupus erythematosus. The current study was designed to compare the oncogenic properties of high dose cyclophosphamide with a low dose therapeutic regimen. Female NZB/NZW mice received life-long therapy with "high dose" cyclophosphamide, 16 mg/kg/day, or "low dose" cyclophosphamide, 5.7 mg/kg/day; control mice received saline. High dose therapy clearly accelerated a p pearance of neoplasms. Seventeen of 19 mice treated with highdose cyclophosphamide developed neoplasms at the mean age of 61 weeks. Fifty-seven percent of these tumors were mammary carcinomas. Neoplasms appeared in all mice treated with low dose; mean longevity in this treatment group was 80 weeks (compared to high dose treated mice, P < 0.001). Carcinomas, pulmonary adenomas, and lymphomas were the most common tumors in mice receiving low dose therapy. Positive tests for ANA were suppressed in high dose treated mice. AntiDNA antibody levels and glomerulonephritis were decreased significantly in both groups of cyclo- phosphamide-treated mice compared to controls. It was concluded t h a t the high daily dose of immunosuppressive drug was related to early oncogenesis in autoimmune NZB/NZW mice.Hybrid New Zealand Black/New Zealand White (NZB/NZW) mice spontaneously develop heterogeneous antinuclear antibodies detected by indirect immunofluorescence (ANA) ( l), specific antibodies to DNA (antiDNA) (2), and immune complex glomerulonephritis (3). Disease is accelerated in females, and 50% of female NZB/NZW mice die with renal failure at 10 months of age (1). These animals are accepted as models of systemic lupus erythematosus (SLE). Early experiments in this laboratory showed that long-term treatment with the potent immunosuppressive drug cyclophosphamide effectively suppressed antiDNA, prevented glomerulonephritis, and prolonged lifespans in female NZB/NZW mice. Ninety-four percent of mice receiving cyclophosphamide, 8 mg/kg/day, developed neoplasms. Only 9% of untreated control mice died with malignancies. Neoplasms appeared in mice receiving therapy with cyclophosphamide for periods mngipg from 30 to 93 weeks (4). The high incidence of malignancies in these old mice suggested that cyclophosphamide caused neoplastic transformation in treated animals. However, it may be argued that NZB/NZW mice developed neoplasms as a consequence of aging after their lives were prolonged artificially by immunosuppressive treatment.In the current study, additional groups of NZB/ NZW mice received life-long therapy with "low dose" cyclophosphamide, 5.7 mg/kg/day, or "high dose" cyclophosphamide, 16 mg/kg/day; control mice received saline. If neoplasms were associated with aging in New

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Section: Therapy Lesionssupporting

confidence: 69%

“…Neoplasms were found in 61% of cyclophosphamide-treated mice. In contrast, none of the mice that received azathioprine-plus-prednisolone developed neoplasms (12).…”

Section: Therapy Lesionsmentioning

confidence: 88%

Accelerated appearance of neoplasms in female nzb/nzw mice treated with high‐dose cyclophosphamide

Walker

Anver

1979

Arthritis & Rheumatism

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“…The use of 15(S)-15 methyl PGE1, a stable derivative of PGE 1 , also protects the NZB/ W mice from lupus nephritis [13,14]. Immunosuppressive and PGE 1 therapy effectively arrests the nephritis prevalent in NZB/W female mice, yet the underlying mechanism is not resolved [14][15][16]. Our data suggests therapy which normalizes the B/T ratio leads to prolonged survival of NZB/W mice.…”

Section: Introductionmentioning

confidence: 91%

“…NZB/W and CD-1 mice were treated with weekly injections of cyclophosphamide. Cyclophosphamide (Mead Johnson and Co., Evansville, IN) was dissolved in PBS and a 25 mg/kg bodyweight dose was administered weekly in a 200 gl volume intraperitoneally [10,15]. The NZB/W and CD-1 mice were weighed weekly and the average weight was used to adjust the weight of cyclophosphamide administered.…”

Section: Treatment Groupsmentioning

confidence: 99%

Cyclophosphamide and 15(S)-15 methyl PGE1 correct the T/B lymphocyte ratios of NZB/NZW mice

et al. 1990

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The lupus of NZB/NZW F1 female mice is associated with immune complex glomerulonephritis and premature death. Cyclophosphamide and 15(S)-15 methyl PGE1 therapy halt disease progression. Fluorescein conjugated antibodies were utilized to label specific leukocytes and the subsets were quantitated using a Fluorescence Activated Cell Sorter. Normal outbred CD-1 female mice showed a decrease in absolute T and B cell numbers with age, but the ratio of T and B cells remained essentially constant through 9 months of age. By contrast the NZB/W female mice showed decreased numbers of total lymphocytes relative to CD-1 controls at all ages. Moreover relative to CD-1s, there was a far greater decrease in T cell numbers (7 x for NZB/W versus 2 x for CD-1) and B cell numbers failed to decrease with age. The characteristic decline in T lymphocyte numbers and relative increase in B cell numbers in NZB/W mice were corrected with cyclophosphamide and PGE1 therapy. However, there was no selective modification of T cell subsets (L3T4+ or Ly2+) with therapy. Our investigation suggests correction of the abnormal T/B cell ratio may be a useful marker of therapeutic activity in NZB/W mice.

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“…Drugs tested in this model include cyclophosphamide [2] and gkicocorticoids [3]. which today are often used for Ihe treatment of severe SLE in the elinic.…”

Section: Introductionmentioning

confidence: 99%

Suppression of autoimmune disease in NZB/W F1 mice by treatment with the novel immunomodulator BTS 63155

Appleby¹,

Telford²,

Naylor³

1993

Clinical and Experimental Immunology

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SUMMARYAutoimmune disease in NZB/W F| mice was treated from 23 weeks of age with the novel immunomodulator BTS 63155 and,, for comparative purposes, the established immunosuppressive agent cyclosporin A. Both drugs significantly improved survival compared wilh untreated controls. Lupus nephritis was also significantly reduced in the drug-treated groups, and this was related to reduced glomerular deposition of IgG. Autoaniibody (ANA) levels were lowered by treatment with cyclosporin A, but not by BTS 63155. This latter finding may indicate a different mode of action for the two drugs. In a long term study, neither drug elTected a complete cure, as autoimmune disease recurred on withdrawal of drug treatment.

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Influence of cyclophosphamide and other immunosuppressive drugs on immune disorders and neoplasia in NZB/NZW MICE

Cited by 77 publications

References 13 publications

Accelerated appearance of neoplasms in female nzb/nzw mice treated with high‐dose cyclophosphamide

Accelerated appearance of neoplasms in female nzb/nzw mice treated with high‐dose cyclophosphamide

Cyclophosphamide and 15(S)-15 methyl PGE1 correct the T/B lymphocyte ratios of NZB/NZW mice

Suppression of autoimmune disease in NZB/W F1 mice by treatment with the novel immunomodulator BTS 63155

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