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1alpha,25-dihydroxyvitamin D(3) (calcitriol) and its analogue, 19-nor-1alpha,25(OH)(2)D(2), potentiate the effects of ionising radiation on human prostate cancer cells.

Dunlap N, Schwartz GG, Eads D, Cramer SD, Sherk AB, John V, Koumenis C - Br. J. Cancer (2003)

Bottom Line: Radiotherapy with external beam radiation or brachytherapy is an established therapeutic modality for prostate cancer.Secondary effects of ionising radiation (IR), for example, bowel and bladder complications, are common.At higher doses of IR, the combination of 1alpha,25-dihydroxyvitamin D(3) and IR or 19-nor-1alpha,25-(OH)(2)D(2) and IR resulted in moderate antagonism.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology, Comprehensive Cancer Center of Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.

ABSTRACT
Radiotherapy with external beam radiation or brachytherapy is an established therapeutic modality for prostate cancer. Approximately 30% of patients with localised prostate cancer relapse at the irradiated site. Secondary effects of ionising radiation (IR), for example, bowel and bladder complications, are common. Thus, the search for biological response modifiers that could potentiate the therapeutic effects of radiation and limit the occurrence of serious side effects is an important task in prostate cancer therapy. 1alpha,25-Dihydroxyvitamin D(3) (calcitriol), the active metabolite of vitamin D, and its analogues are under investigation for the treatment of several malignancies including prostate cancer. Here, we report that 1alpha,25-dihydroxyvitamin D(3) and its less calcaemic analogue 19-nor-1alpha,25-(OH)(2)D(2) (Zemplar) act synergistically with IR to inhibit the growth of the human prostate cancer cells in vitro. 1alpha,25-dihydroxyvitamin D(3) potentiated IR-induced apoptosis of LNCaP cells, and nanomolar doses of 1alpha,25-dihydroxyvitamin D(3) and 19-nor-1alpha,25-(OH)(2)D(2) showed synergistic inhibition of growth of LNCaP cells at radiobiologically relevant doses of IR (1-2 Gy). At higher doses of IR, the combination of 1alpha,25-dihydroxyvitamin D(3) and IR or 19-nor-1alpha,25-(OH)(2)D(2) and IR resulted in moderate antagonism. The synergistic effect at radiobiologically relevant doses of radiation suggests that a combination of 1alpha,25-dihydroxyvitamin D(3) or 19-nor-1alpha,25-(OH)(2)D(2) with IR could permit a reduction in the dose of radiation given clinically and thus potentially reduce treatment-related morbidity.

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Effects of combined treatments of 1α,25(OH)2D3 and IR on primary prostate cells. Cells were isolated from patients who underwent radical prostatectomy at WFU as described in Materials and Methods. Cells were plated into 35 mm dishes and treated with 1 nM 1α,25(OH)2D3. After 24 h, cells were irradiated in a caesium irradiator with the indicated doses and returned to 37°C for growth for an additional 10–12 days. At the end of treatment, cells were trypsinised and counted. Control cells received only 0.1% ethanol. Experiments were performed in triplicate. The example shown is from the WFU10Ca, a cancer-derived primary strain. Similar results were obtained with two other cancer-derived and three normal prostate-derived strains.
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fig4: Effects of combined treatments of 1α,25(OH)2D3 and IR on primary prostate cells. Cells were isolated from patients who underwent radical prostatectomy at WFU as described in Materials and Methods. Cells were plated into 35 mm dishes and treated with 1 nM 1α,25(OH)2D3. After 24 h, cells were irradiated in a caesium irradiator with the indicated doses and returned to 37°C for growth for an additional 10–12 days. At the end of treatment, cells were trypsinised and counted. Control cells received only 0.1% ethanol. Experiments were performed in triplicate. The example shown is from the WFU10Ca, a cancer-derived primary strain. Similar results were obtained with two other cancer-derived and three normal prostate-derived strains.

Mentions: We also wanted to test the effects of 1α,25(OH)2D3 on the response of primary prostate tumour cells to IR. Previously, it was shown that 1α,25(OH)2D3 inhibited the growth of primary prostatic cells in a dose-dependent manner (Peehl et al, 1994; Barreto et al, 2000). We first tested a range of doses of 1α,25(OH)2D3 for its ability to inhibit cell growth in a variety of normal and cancer-derived cell clones (data not shown). A dose of 1 nM had only a minimal effect on the growth of all strains tested. We next tested the effects of combined treatments of 1 nM 1α,25(OH)2D3 with increasing doses of IR. As shown in Figure 4Figure 4


1alpha,25-dihydroxyvitamin D(3) (calcitriol) and its analogue, 19-nor-1alpha,25(OH)(2)D(2), potentiate the effects of ionising radiation on human prostate cancer cells.

Dunlap N, Schwartz GG, Eads D, Cramer SD, Sherk AB, John V, Koumenis C - Br. J. Cancer (2003)

Effects of combined treatments of 1α,25(OH)2D3 and IR on primary prostate cells. Cells were isolated from patients who underwent radical prostatectomy at WFU as described in Materials and Methods. Cells were plated into 35 mm dishes and treated with 1 nM 1α,25(OH)2D3. After 24 h, cells were irradiated in a caesium irradiator with the indicated doses and returned to 37°C for growth for an additional 10–12 days. At the end of treatment, cells were trypsinised and counted. Control cells received only 0.1% ethanol. Experiments were performed in triplicate. The example shown is from the WFU10Ca, a cancer-derived primary strain. Similar results were obtained with two other cancer-derived and three normal prostate-derived strains.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2376931&req=5

fig4: Effects of combined treatments of 1α,25(OH)2D3 and IR on primary prostate cells. Cells were isolated from patients who underwent radical prostatectomy at WFU as described in Materials and Methods. Cells were plated into 35 mm dishes and treated with 1 nM 1α,25(OH)2D3. After 24 h, cells were irradiated in a caesium irradiator with the indicated doses and returned to 37°C for growth for an additional 10–12 days. At the end of treatment, cells were trypsinised and counted. Control cells received only 0.1% ethanol. Experiments were performed in triplicate. The example shown is from the WFU10Ca, a cancer-derived primary strain. Similar results were obtained with two other cancer-derived and three normal prostate-derived strains.
Mentions: We also wanted to test the effects of 1α,25(OH)2D3 on the response of primary prostate tumour cells to IR. Previously, it was shown that 1α,25(OH)2D3 inhibited the growth of primary prostatic cells in a dose-dependent manner (Peehl et al, 1994; Barreto et al, 2000). We first tested a range of doses of 1α,25(OH)2D3 for its ability to inhibit cell growth in a variety of normal and cancer-derived cell clones (data not shown). A dose of 1 nM had only a minimal effect on the growth of all strains tested. We next tested the effects of combined treatments of 1 nM 1α,25(OH)2D3 with increasing doses of IR. As shown in Figure 4Figure 4

Bottom Line: Radiotherapy with external beam radiation or brachytherapy is an established therapeutic modality for prostate cancer.Secondary effects of ionising radiation (IR), for example, bowel and bladder complications, are common.At higher doses of IR, the combination of 1alpha,25-dihydroxyvitamin D(3) and IR or 19-nor-1alpha,25-(OH)(2)D(2) and IR resulted in moderate antagonism.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology, Comprehensive Cancer Center of Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.

ABSTRACT
Radiotherapy with external beam radiation or brachytherapy is an established therapeutic modality for prostate cancer. Approximately 30% of patients with localised prostate cancer relapse at the irradiated site. Secondary effects of ionising radiation (IR), for example, bowel and bladder complications, are common. Thus, the search for biological response modifiers that could potentiate the therapeutic effects of radiation and limit the occurrence of serious side effects is an important task in prostate cancer therapy. 1alpha,25-Dihydroxyvitamin D(3) (calcitriol), the active metabolite of vitamin D, and its analogues are under investigation for the treatment of several malignancies including prostate cancer. Here, we report that 1alpha,25-dihydroxyvitamin D(3) and its less calcaemic analogue 19-nor-1alpha,25-(OH)(2)D(2) (Zemplar) act synergistically with IR to inhibit the growth of the human prostate cancer cells in vitro. 1alpha,25-dihydroxyvitamin D(3) potentiated IR-induced apoptosis of LNCaP cells, and nanomolar doses of 1alpha,25-dihydroxyvitamin D(3) and 19-nor-1alpha,25-(OH)(2)D(2) showed synergistic inhibition of growth of LNCaP cells at radiobiologically relevant doses of IR (1-2 Gy). At higher doses of IR, the combination of 1alpha,25-dihydroxyvitamin D(3) and IR or 19-nor-1alpha,25-(OH)(2)D(2) and IR resulted in moderate antagonism. The synergistic effect at radiobiologically relevant doses of radiation suggests that a combination of 1alpha,25-dihydroxyvitamin D(3) or 19-nor-1alpha,25-(OH)(2)D(2) with IR could permit a reduction in the dose of radiation given clinically and thus potentially reduce treatment-related morbidity.

Show MeSH
Related in: MedlinePlus