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Updated: Jul 30, 2026
Changes in Mammary Gland Morphology and Breast Cancer Risk in Rats
Published on: October 16, 2010
Effects of Seocalcitol (EB1089) on nitrosomethyl urea-induced rat mammary tumors
K W Colston1, G Pirianov, E Bramm
1Department of Oncology, Gastroenterology, Endocrinology and Metabolism, St George's Hospital Medical School, London, UK. kcolston@sghms.ac.uk
Abstract:
Although 1,25-dihydroxyvitamin D3 is a potent cell-differentiating agent, its use in cancer prevention or therapy is precluded because it induces hypercalcemia. Synthetic analogs have been developed which inhibit tumor progression in animal models of breast cancer. One analog, Seocalcitol (EB1089) has been shown to be effective in causing regression of N-methyl-nitrosourea-induced rat mammary tumors. However, at the most effective oral dose, a significant increase in serum and urinary calcium levels were observed. In order to compare the efficacy of different dosing schedules of Seocalcitol, rats were treated either 6 times weekly (1 microg/kg) or by intermittent dosing to achieve the same total weekly dose. All dosing schedules of Seocalcitol were effective in inhibiting tumor progression. Once daily dosing was significantly more effective than intermittent dosing but was associated with a greater rise in serum calcium concentration. In order to evaluate alternative treatment strategies to limit calcemic effects, we assessed the efficacy of limiting vitamin D-induced hypercalcemia using bisphosphonates. Seocalcitol (2.5 microg/kg daily p.o. for 4 weeks) alone and in combination with pamidronate (APD 0.4 mg/kg per day s.c.) or the same dose of the bisphosphonate EB 1053 caused substantial tumor regression. No statistically significant difference was seen between combination treatment and Seocalcitol treatment alone. Co-treatment with APD or EB 1053 did not limit the rise in serum calcium induced by Seocalcitol alone. Cessation of treatment or administration of a lower dose (1microg/kg twice weekly) reversed hypercalcemia, hypercalciuria and weight loss induced by high dose Seocalcitol. However, reduction in tumor volume was maintained in the majority of animals.
Insights
Synthetic vitamin D analogs like Seocalcitol show promise in treating breast cancer by inhibiting tumor growth. However, hypercalcemia remains a challenge, though dose adjustments and bisphosphonates did not fully resolve it.
Area of Science:
- Oncology
- Pharmacology
- Endocrinology
Background:
- 1,25-dihydroxyvitamin D3 is a potent cell differentiator but causes hypercalcemia, limiting its cancer therapeutic use.
- Synthetic vitamin D analogs, such as Seocalcitol (EB1089), inhibit tumor progression in preclinical breast cancer models.
- Seocalcitol effectively regresses rat mammary tumors but causes significant hypercalcemia at effective doses.
Purpose of the Study:
- To compare the efficacy of different Seocalcitol dosing schedules on tumor progression and hypercalcemia.
- To evaluate bisphosphonates (pamidronate and EB 1053) as a strategy to mitigate Seocalcitol-induced hypercalcemia.
- To assess the reversibility of Seocalcitol's side effects and maintenance of tumor regression.
Main Methods:
- Rats with N-methyl-nitrosourea-induced mammary tumors were treated with Seocalcitol via different dosing schedules (6 times weekly vs. intermittent).
- Seocalcitol was administered alone or in combination with bisphosphonates (pamidronate or EB 1053) to assess efficacy and calcemic effects.
- Serum calcium, urinary calcium, and tumor volume were monitored throughout the study.
Main Results:
- All Seocalcitol dosing schedules inhibited tumor progression; once-daily dosing was more effective but increased serum calcium more than intermittent dosing.
- Combination therapy with bisphosphonates did not significantly improve tumor regression compared to Seocalcitol alone and did not limit hypercalcemia.
- Cessation of treatment or dose reduction reversed hypercalcemia and hypercalciuria while maintaining tumor volume reduction in most animals.
Conclusions:
- Seocalcitol demonstrates efficacy in inhibiting breast cancer tumor progression, with daily dosing being more effective.
- Bisphosphonates do not mitigate the hypercalcemic side effects of Seocalcitol.
- Hypercalcemia and associated side effects can be reversed by adjusting Seocalcitol dosage or treatment cessation, with sustained tumor control observed.
