Background: In recent years, the relevance of vitamin D receptor (VDR) gene restriction fragment length polymorphisms for
various types of cancer has been investigated by a great number of studies. ...It has been hypothesized that VDR polymorphisms
may influence both the risk of cancer occurrence and prognosis. However, studies investigating the associations between specific
VDR polymorphisms and cancer often show controversial results. We have now performed a systematic review of the literature
to analyse the relevance of VDR polymorphisms for individual malignancies, including cancer of the skin, prostate, breast,
colon, ovary, kidney and bladder. Materials and Methods: An analysis of studies evaluating the association between vitamin
D receptor gene polymorphisms Fok1, Bsm1, Taq1, Apa1, and Cdx2, poly (A) and Bgl1 as well as some haplotype combinations and
cancer risk has been performed. Data were extracted from PubMed using the key words VDR polymorphism in combination with breast
cancer, prostate cancer, skin cancer, colorectal cancer, ovarian cancer, renal cell carcinoma or bladder cancer. Results:
This analysis was performed with the intent of giving an up-to-date overview of all data concerning the relevance of VDR polymorphisms
for cancer. Obviously, at present it is still not possible to make any definitive statements about the importance of the VDR
genotype for cancer occurrence. It seems probable that interactions with other factors such as calcium and vitamin D intake, 25(OH)D plasma levels and UV radiation exposure play a decisive role in cancer occurrence and should not be underestimated. Other
risk factors such as obesity, smoking status, parity status, energy intake and others are also frequently mentioned as being
more or less important for carcinogenesis depending on the VDR genotype. Moreover, it is often noticed that the same VDR polymorphism
has a different effect depending on the type of cancer, or may be only decisive for more or less aggressive staging of the
tumour. Conclusion: Significant associations with VDR polymorphisms have been reported in cancer of the breast (Fok1, Bsm1,
Taq1, Apa1, poly (A)), prostate (Fok1, Bsm1, Taq1, poly (A)), skin (Fok1, Bsm1, A-1210), colorectum (Fok1, Bsm1), ovary (Fok1,
Apa1) and bladder (Fok1), and in renal cell carcinoma (Taq1, Apa1). However, conflicting data have been reported for most
malignancies. After careful evaluation of the actual literature, it can be summarized that data indicating an association
of VDR polymorphisms and cancer risk are strongest for breast cancer (Bsm1, Fok1), prostate cancer (Fok1) and malignant melanoma
(MM) (Fok1). Data indicating an association of VDR polymorphisms and cancer prognosis are strongest for prostate cancer (Fok1),
breast cancer (Bsm1, Taq1), MM (Bsm1) and renal cell carcinoma (Taq1).
To determine the predictive value of the angiogenic serum factors angiogenin, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and interleukin-8 (IL-8) for the ...prognosis of patients with malignant melanoma.
Angiogenin, VEGF, bFGF, and IL-8 were measured in sera of 125 melanoma patients with different stages of disease and with or without current therapy including interferon alfa and different cytostatics in comparison with 30 healthy controls using enzyme-linked immunosorbent assay.
Serum levels of angiogenin, VEGF, bFGF, and IL-8 were significantly increased in melanoma patients compared with healthy controls. Elevated serum concentrations of VEGF, bFGF, and IL-8 were associated with advanced disease stages and tumor burden. Cytostatic therapy of patients was accompanied by increased serum levels of angiogenin, bFGF, and IL-8. As shown by univariate analysis, elevated serum levels of VEGF (P = .0001 and .0036), bFGF (P < .00005 and < .00005), and IL-8 (P < .00005 and < .00005) were strongly correlated with a poor overall and progression-free survival, respectively. Multivariate analysis revealed stage of disease (P = .0238), tumor burden (P = .0347), VEGF (P = .0036), bFGF (P = .0252), and IL-8 (P = .0447) as independent predictive factors of overall survival. Tumor burden (P = .0081), VEGF (P = .0245), and IL-8 (P = .0089) were found as independent predictive factors of progression-free survival.
Our data suggest that the angiogenic serum factors VEGF, bFGF, and IL-8 are useful predictive markers for overall and progression-free survival in melanoma patients.
Purpose: In vitro sensitivity assays are promising tools to predict the individual outcome of different chemotherapy regimens. However, a direct
association between in vitro and in vivo ...chemosensitivity has to be shown by clinical studies. This multicenter phase II trial was aimed to investigate the efficacy
of a sensitivity-directed, first-line chemotherapy in metastasized melanoma patients, and to prove an association between
in vitro sensitivity and therapy outcome.
Patients and Methods: The primary study end point was objective response; secondary end points were safety, overall survival, and progression-free
survival. Viable tumor cells obtained from metastatic lesions were tested for chemosensitivity to seven single drugs and five
drug combinations using an ATP-based luminescence viability assay.
Results: Out of 82 recruited patients (intention-to-treat), 57 received assay-directed chemotherapy and 53 were evaluable for all
study end points (per protocol). The drug combinations used were gemcitabine + treosulfan, paclitaxel + cisplatin, paclitaxel
+ doxorubicin, and gemcitabine + cisplatin. The per protocol population could be divided into 22 (42%) chemosensitive and
31 (58%) chemoresistant patients by an arbitrary chemosensitivity index. Objective response was 36.4% in chemosensitive patients
compared with 16.1% in chemoresistant patients ( P = 0.114); progression arrest (complete response + partial response + stable disease) was 59.1% versus 22.6% ( P = 0.01). Chemosensitive patients showed an increased overall survival of 14.6 months compared with 7.4 months in chemoresistant
patients ( P = 0.041).
Conclusion: In vitro chemosensitivity testing may be worthy of further exploration to see if it could be a useful tool to predict the outcome
of melanoma patients treated with a sensitivity-directed chemotherapy. Therefore, these preliminary results will be evaluated
by a planned phase III trial using a randomized, standard-regimen controlled setting.
Temozolomide (TMZ) has shown efficacy in metastatic melanoma equal to that of dacarbazine (DTIC), the standard chemotherapeutic agent for melanoma. As the combination with interferon-alfa (IFN-alpha) ...appears superior to single-agent DTIC regarding response rates, the purpose of this study was to compare TMZ alone and TMZ plus IFN-alpha in terms of objective response (OR), overall survival, and safety in a prospective, randomized, multicenter trial.
Two hundred ninety-four patients with untreated stage IV metastatic melanoma (American Joint Committee on Cancer staging system) were randomly assigned to receive either oral TMZ alone (200 mg/m2/day; days 1 through 5 every 28 days) or in combination with subcutaneous IFN-alpha (5 MU/m2; days 1, 3, and 5 every week).
Two hundred eighty-two patients were eligible for an intent-to-treat analysis, 271 patients were treated per protocol. In the TMZ + IFN-alpha arm, 33 (24.1%) of 137 patients responded to therapy (partial or complete remission) whereas in the monotherapy arm, in 18 (13.4%) of 134 patients, a response was evident. Thus, the response rate was significantly higher in the combination arm (P = .036). Median survival time was 8.4 months for patients treated with TMZ (95% CI, 7.07 to 9.27) and 9.7 months for those treated with the combination (95% CI, 8.26 to 11.18; P = .16). Dose modifications and interval prolongations due to hematologic toxicity were significantly more frequent in the TMZ + IFN-alpha arm (P < .001).
In metastatic melanoma treatment with TMZ + IFN-alpha leads to a significantly superior OR rate compared to treatment with TMZ alone, which did not translate into prolonged survival in our study population.
The expression and signaling of the vitamin D receptor (VDR) and peroxisome proliferator-activated receptor (PPAR) α, δ, γ
was investigated in the melanoma cell line MeWo. Using real-time PCR, the ...mRNA of the nuclear receptors (NR) was detected.
The strongest expression was found for the VDR, approximately 3-fold higher compared to the expression of PPARα or PPARδ,
and the weakest expression was for PPARγ. After treatment with corresponding ligands, the expression of the VDR, PPARα and
PPARδ was elevated up to 5-fold, while the PPARγ expression was not significantly affected. Treatment with 1α,25-dihydroxyvitamin
D 3 (1,25(OH) 2 D 3 , calcitrol) resulted in 40% inhibition of MeWo cell proliferation, that was associated with a 5-fold increase in VDR mRNA.
Interestingly, cell proliferation was differentially modulated by treatment with the PPAR ligands. While docosahexaenoic acid
(DHA) treatment resulted in a statistically significant increase (approximately 10%), the other PPAR ligands inhibited MeWo
cell proliferation. GW501516 (PPARδ ligand) and WY14643 (PPARα ligand) both had an antiproliferative effect of approximately
10%. These antiproliferative effects were not associated with modulation of PPARα or PPARδ expression. In contrast, stimulation
of MeWo proliferation by DHA was associated with a 3- and 4-fold increase in the expression of PPARα and PPARδ, respectively.
Analyzing the cross-talk between the VDR and PPAR signaling pathways, the 1,25(OH) 2 D 3 treatment resulted in an approximately 2-fold increase in expression of PPARα and PPARδ, while the expression of PPARγ was
unaffected. Treatment with GW501516 and WY14643 resulted in an increase in the VDR expression (2-fold after 120 h). The simultaneous
treatment with 1,25(OH) 2 D 3 partially antagonised the DHA- and alpha-linolenicacid (ALA)-induced up-regulation of PPAR expression. In contrast, treatment
with the PPAR ligands had no pronounced effect on the 1,25(OH) 2 D 3 -induced increase in VDR expression. Simultaneous treatment with the PPAR ligands bezafibrate or ALA resulted in an up to
6-fold reduction of the 1,25(OH) 2 D 3 -induced elevation of the 1α,25-dihydroxyvitamin D 3 -24-hydroxylase (CYP24A1) expression. Simultaneous treatment with the PPAR ligands and 1,25(OH) 2 D 3 resulted in only marginal modulation of 1,25(OH) 2 D 3 -induced inhibition of cell proliferation. However, simultaneous treatment with bezafibrate and 1,25(OH) 2 D 3 resulted in a statistically significant partial antagonisation of the 1,25(OH) 2 D 3 -induced inhibition of MeWo cell proliferation. In conclusion, PPAR and VDR have a role in growth regulation in melanoma cells
and functionally relevant cross-talk between these nuclear signaling pathways is indicated, but not at the level of cell proliferation,
where 1,25(OH) 2 D 3 has a dominant effect.
Peroxisome proliferator-activated receptor (PPAR) and vitamin D receptor (VDR) signaling pathways regulate a multitude of genes that are of importance for a multitude of cellular functions including ...cell proliferation, cell differentiation, immune responses and apoptosis. Ligands and other agents influencing the PPAR and VDR signaling pathways have been shown to reveal chemopreventive potential by mediating tumor suppressive activities in a variety of human cancers. Use of these compounds may represent a potential novel strategy to prevent melanoma pathogenesis and to inhibit melanoma progression. We recently showed that 1,25-dihydroxyvitamin D
3 and some of the investigated PPAR ligands inhibited proliferation of the human melanoma cell line MeWo. In addition to this, our results gave an indication of an interconnection of the PPAR and VDR signaling pathways at the level of cross-regulation of their respective transcription factor mRNA levels. The provided link between VDR and PPAR may play an important role in treatment and prevention of melanoma. This review summarizes the currently available data on the roles of the PPARs and the VDR in pathogenesis and progression of melanoma as well as their role as promising future therapeutic targets.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We studied effects of 1,25-dihydroxyvitamin D3 1,25(OH)2D3, its analog seocalcitol (EB 1089), and 25-hydroxyvitamin D3 25(OH)D3, on the growth of seven melanoma cell lines. While three cell lines ...(MeWo, SK-Mel-28, SM) responded to antiproliferative effects of active vitamin D analogs, the others (SK-Mel-5, SK-Mel-25, IGR, MelJuso) were resistant. A strong induction (7000-fold) of 1,25-dihydroxyvitamin D-24-hydroxylase (24OHase, CYP24) mRNA was detected in responsive cell lines along with 1,25(OH)2D3-treatment, indicating functional integrity of vitamin D receptor (VDR)-mediated transcription. In contrast, induction of 24OHase was much lower in resistant melanoma cells (70-fold). VDR mRNA was induced up to 3-fold both in responsive and resistant cell lines along with 1,25(OH)2D3-treatment. RNA for vitamin D-activating enzymes vitamin D-25-hydroxylase (25OHase, CYP27A1) and 25-hydroxyvitamin D-1α-hydroxylase (1αOHase, CYP27B1) was detected in all melanoma cell lines analyzed, additionally we show splicing variants of 1αOHase in SK-Mel-28 cells. Expression of 25OHase and 1αOHase was marginally modulated along with treatment. Proliferation of melanoma cells was not inhibited by treatment with 25(OH)D3, indicating no significant stimulation of endogeneous production of antiproliferative acting 1,25(OH)2D3. In conclusion, we characterize the vitamin D endocrine system in melanoma cells and demonstrate that the majority of melanoma cell lines analyzed is resistant to antiproliferative effects of 1,25(OH)2D3. It can be speculated that these alterations are of importance for pathogenesis and growth of metastasizing malignant melanoma. Additionally, our findings indicate that only a minority of cases with metastasizing melanoma may represent a promising target for palliative treatment with new vitamin D analogs that exert little calcemic side effects or for pharmacological modulation of 1,25(OH)2D3-synthesis/metabolism.
The primary treatment of a melanoma is surgical excision. An excisional biopsy is preferred, and safety margins of 1 cm for tumor thickness up to 2 mm and 2 cm for higher tumor thickness should be ...applied either at primary excision or in a two-step procedure. When dealing with facial, acral or anogenital melanomas, micrographic control of the surgical margins may be preferable to allow reduced safety margins and conservation of tissue. The sentinel lymph node biopsy should be performed in patients whose primary melanoma is thicker than 1.0 mm and this operation should be performed in centers where both the operative and nuclear medicine teams are experienced. In clinically identified lymph node metastases, radical lymph node dissection is considered standard therapy. If distant metastases involve just one internal organ and operative removal is feasible, then surgery should be seen as therapy of choice. Radiation therapy for the primary treatment of melanoma is indicated only in those cases in which surgery is impossible or not reasonable. In regional lymph nodes, radiation therapy is usually recommended when excision is not complete (R1 resection) or if the nodes are inoperable. In distant metastases, radiation therapy is particularly indicated in bone metastases, brain metastases and soft tissue metastases.
1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is the biologically active metabolite of vitamin D and has been shown to regulate the growth of various cell types. There are two principal enzymes involved in ...the formation of circulating 1,25(OH)2D3 from vitamin D, the vitamin D 25-hydroxylase (25-OHase) and the 1alpha-hydroxylase (1alpha-OHase). Recently, extrarenal activity of 1alpha-OHase has been reported in various cell types. The aim of this study was to analyze expression of VDR and the main enzymes involved in the synthesis and metabolism of calcitriol in gynecological malignancies and corresponding normal tissue. Expression of VDR, 25-OHase, 1alpha-OHase, and 24-OHase was analyzed in breast carcinomas (BC), ovarian cancer (OC), cervix carcinomas (CC) and normal corresponding tissues using real-time PCR and specific hybridization probes as well as using immunohistochemistry. RNA for VDR, 1alpha-OHase, 24-OHase and 25-OHase was up-regulated in breast cervical and ovarian carcinomas as compared to normal tissue. VDR immunoreactivity was increased in breast and ovarian cancer and in cervix carcinomas as compared to normal corresponding tissue. Our findings indicate that cervical carcinomas, breast cancer and ovarian cancer may be considered as potential targets for prevention or therapy with new vitamin D analogs that exert little or no calcemic side effects or by pharmacological modulation of 1,25(OH)2D3 synthesis and metabolism in these tumor cells.
PDF
