Inhibition of prostate cancer metastasis in vivo: A comparison of 1,25- dihydroxyvitamin D (calcitriol) and EB1089

Bal L. Lokeshwar, Gary G. Schwartz, Marie G. Selzer, Kerry L. Burnstein, Sen Hong Zhuang, Norman L. Block, Lise Binderup

Research output: Contribution to journalArticle

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Abstract

The steroid hormone 1,25-dihydroxyvitamin D [1,25(OH)2D, also known as calcitriol] is known to inhibit the proliferation and to promote the differentiation of human prostate cancer cells. Additionally, we showed that 1,25(OH)2D markedly inhibits the invasiveness of human prostate cancer cells in vitro (G.G. Schwartz et al., Cancer Epidemiol. Biomark. Prev., 6: 727- 732, 1997). These properties support the use of 1,25(OH)2D as differentiation therapy in prostate cancer. However, the use of 1,25(OH)2D in vivo is limited by the risk of hypercalcemia. We therefore compared the effects of 1,25(OH)2D and of EB1089, an analogue of 1,25(OH)2D with reduced calcemic effects, in an in vivo model of androgen-insensitive metastatic prostate cancer, the rat Dunning MAT LyLu prostate cancer model. Tumor growth and metastasis were studied using Copenhagen rats given s.c. injections of MAT LyLu cells. Fifty male rats were divided into five groups of 10 rats each. Four experimental groups received i.p. injections of low and high doses of 1,25(OH)2D and EB1089 (0.5 and 1.0 μg/kg, low and high, respectively). A control group received injections of vehicle only. Tumor volumes were measured three times per week. Rats were weighed weekly. The number of metastases to the lungs and the extent of hypercalcemia were evaluated. Compared with controls, tumor volumes were significantly smaller in all experimental groups. Similarly, the number of lung metastases (number of foci/lung) was reduced markedly by both 1,25(OH)2D and EB1089. Control rats developed 22.7 (± 1.98 SE) tumor foci per lung. Rats treated with 1,25(OH)2D and with EB1089 (1.0 μg/kg) developed 10.4 (± 2.81) and 7.70 (± 1.29) tumor foci, respectively (P < 0.001 and P < 0.0001, respectively; drug versus control). Compared with controls (10.79 ± 0.1 mg/dl), serum calcium levels were significantly elevated in both 1,25(OH)2D and EB1089- treated rats (P < 0.01). However, EB1089 was significantly less calcemic than 1,25(OH)2D (12.59 ± 0.21 mg/dl versus 14.47 ± 0.46 mg/dl; 1.0 μg/kg; P < 0.001). Rats treated with 1,25(OH)2D showed marked weight loss: 20.0 ± 1.9% and 26.3 ± 1.7% of their initial weight (low and high doses, respectively, P < 0.001). Weight loss was significantly lower in rats treated with EB1089 at the high dose 8.4 (± 2.9)%. Moreover, rats treated with low-dose EB1089 gained 5.2 (± 3.7)% of their initial weight. In conclusion, 1,25(OH)2D and EB1089 showed marked and equivalent inhibition of prostate cancer metastasis in vivo. EB1089 was significantly less calcemic than 1,25(OH)2D and did not induce severe weight loss. This is the first report of a vitamin D analogue that significantly inhibits prostate cancer metastasis in vivo and that does so without producing cachexia or unacceptable hypercalcemia.

Original languageEnglish (US)
Pages (from-to)241-248
Number of pages8
JournalCancer Epidemiology Biomarkers and Prevention
Volume8
Issue number3
StatePublished - Mar 1 1999

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Calcitriol
Prostatic Neoplasms
Neoplasm Metastasis
Hypercalcemia
Weight Loss
Lung
Tumor Burden
Injections
Neoplasms
seocalcitol
1,25-dihydroxyvitamin D
Weights and Measures
Cachexia
Drug and Narcotic Control
Vitamin D
Androgens
Steroids
Hormones
Calcium

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

Cite this

Lokeshwar, B. L., Schwartz, G. G., Selzer, M. G., Burnstein, K. L., Zhuang, S. H., Block, N. L., & Binderup, L. (1999). Inhibition of prostate cancer metastasis in vivo: A comparison of 1,25- dihydroxyvitamin D (calcitriol) and EB1089. Cancer Epidemiology Biomarkers and Prevention, 8(3), 241-248.

Inhibition of prostate cancer metastasis in vivo : A comparison of 1,25- dihydroxyvitamin D (calcitriol) and EB1089. / Lokeshwar, Bal L.; Schwartz, Gary G.; Selzer, Marie G.; Burnstein, Kerry L.; Zhuang, Sen Hong; Block, Norman L.; Binderup, Lise.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 8, No. 3, 01.03.1999, p. 241-248.

Research output: Contribution to journalArticle

Lokeshwar, BL, Schwartz, GG, Selzer, MG, Burnstein, KL, Zhuang, SH, Block, NL & Binderup, L 1999, 'Inhibition of prostate cancer metastasis in vivo: A comparison of 1,25- dihydroxyvitamin D (calcitriol) and EB1089', Cancer Epidemiology Biomarkers and Prevention, vol. 8, no. 3, pp. 241-248.
Lokeshwar, Bal L. ; Schwartz, Gary G. ; Selzer, Marie G. ; Burnstein, Kerry L. ; Zhuang, Sen Hong ; Block, Norman L. ; Binderup, Lise. / Inhibition of prostate cancer metastasis in vivo : A comparison of 1,25- dihydroxyvitamin D (calcitriol) and EB1089. In: Cancer Epidemiology Biomarkers and Prevention. 1999 ; Vol. 8, No. 3. pp. 241-248.
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T2 - A comparison of 1,25- dihydroxyvitamin D (calcitriol) and EB1089

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AU - Schwartz, Gary G.

AU - Selzer, Marie G.

AU - Burnstein, Kerry L.

AU - Zhuang, Sen Hong

AU - Block, Norman L.

AU - Binderup, Lise

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N2 - The steroid hormone 1,25-dihydroxyvitamin D [1,25(OH)2D, also known as calcitriol] is known to inhibit the proliferation and to promote the differentiation of human prostate cancer cells. Additionally, we showed that 1,25(OH)2D markedly inhibits the invasiveness of human prostate cancer cells in vitro (G.G. Schwartz et al., Cancer Epidemiol. Biomark. Prev., 6: 727- 732, 1997). These properties support the use of 1,25(OH)2D as differentiation therapy in prostate cancer. However, the use of 1,25(OH)2D in vivo is limited by the risk of hypercalcemia. We therefore compared the effects of 1,25(OH)2D and of EB1089, an analogue of 1,25(OH)2D with reduced calcemic effects, in an in vivo model of androgen-insensitive metastatic prostate cancer, the rat Dunning MAT LyLu prostate cancer model. Tumor growth and metastasis were studied using Copenhagen rats given s.c. injections of MAT LyLu cells. Fifty male rats were divided into five groups of 10 rats each. Four experimental groups received i.p. injections of low and high doses of 1,25(OH)2D and EB1089 (0.5 and 1.0 μg/kg, low and high, respectively). A control group received injections of vehicle only. Tumor volumes were measured three times per week. Rats were weighed weekly. The number of metastases to the lungs and the extent of hypercalcemia were evaluated. Compared with controls, tumor volumes were significantly smaller in all experimental groups. Similarly, the number of lung metastases (number of foci/lung) was reduced markedly by both 1,25(OH)2D and EB1089. Control rats developed 22.7 (± 1.98 SE) tumor foci per lung. Rats treated with 1,25(OH)2D and with EB1089 (1.0 μg/kg) developed 10.4 (± 2.81) and 7.70 (± 1.29) tumor foci, respectively (P < 0.001 and P < 0.0001, respectively; drug versus control). Compared with controls (10.79 ± 0.1 mg/dl), serum calcium levels were significantly elevated in both 1,25(OH)2D and EB1089- treated rats (P < 0.01). However, EB1089 was significantly less calcemic than 1,25(OH)2D (12.59 ± 0.21 mg/dl versus 14.47 ± 0.46 mg/dl; 1.0 μg/kg; P < 0.001). Rats treated with 1,25(OH)2D showed marked weight loss: 20.0 ± 1.9% and 26.3 ± 1.7% of their initial weight (low and high doses, respectively, P < 0.001). Weight loss was significantly lower in rats treated with EB1089 at the high dose 8.4 (± 2.9)%. Moreover, rats treated with low-dose EB1089 gained 5.2 (± 3.7)% of their initial weight. In conclusion, 1,25(OH)2D and EB1089 showed marked and equivalent inhibition of prostate cancer metastasis in vivo. EB1089 was significantly less calcemic than 1,25(OH)2D and did not induce severe weight loss. This is the first report of a vitamin D analogue that significantly inhibits prostate cancer metastasis in vivo and that does so without producing cachexia or unacceptable hypercalcemia.

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