November 20, 2009: Source: World J Gastroenterol 2009 July 21, 1915 (1927): 3349-3354
Een bepaalde vorm van vitamine D - 1 a, 25 (OH) 2 D ((Paricalcitol) heeft een positief effect op de preventie, maar ook bij de behandeling van alvleesklierkanker. Hier is het volledige onderzoeksverslag met verwijzingen naar andere studies... deze vorm van vitamine D benadert de beste vitamine D welke door zonlicht worden gevormd in het eigen lichaam. Voor mij is het te ingewikkeld om dit studierapport te vertalen, maar u kunt het uitprinten en neem contact op met uw begeleidende arts. Goed gekwalificeerde orthomoleculaire artsen weten precies welke vorm van vitamine D hier bedoeld wordt.
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Kun-Chun Chiang, Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan, China
Tai C. Chen, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, United States
Author contributions: KC Chiang wrote this script, Chen TC revised the manuscript.
Correspondence to: Tai C. Chen, Professor, Boston University School of Medicine, 715 Albany Street, Rm M-1022, Boston, MA 02118, United States. taichen@bu.edu
Telephone: +1-617-6384543 Fax: +1-617-6388898
Received: April 9, 2009 Revised: June 3, 2009
Accepted: June 10, 2009
Published online: July 21, 2009
Abstract
Pancreatic cancer is ranked fifth among cancer-related deaths worldwide with a 5-year survival rate of less Than 5%. Currently, surgery is the only effective therapy. However, most patiënten are diagnosed in the late stage and are not receiving Suitable for Curative surgery. Over more, doesnâ pancreatic cancer responded well to traditional chemotherapy and radiotherapy, leaving little effective treatment for advanced pancreatic cancer cases. 1 a ,25-dihydroxyvitamin D 3 [1 a, 25 (OH) 2 D 3], the Biologically active form of vitamin D 3, was consistently Originally Identified studies of calcium and bone metabolism, though it is now recognized thats it Exert biological effects in almost every tissue in the body. Abundant evidence HAS Shown That a 1, 25 (OH) 2 D 3 HAS antiproliferative, apoptotic, pro-differentiation and antiangiogensis effects in many types of cancer cells i n vivo and in vitro, include breast, prostate, and colon. Similarly, the antitumor growth effect or a 1, 25 (OH) 2 D 3 on pancreatic cells demonstrated Has Been. The clinical use of a 1, 25 (OH) 2 D 3 has been impeded by the lethal side effects of hypercalcemia and hypercalciuria. Therefore, 1 a, 25 (OH) 2 D 3 analogs, Which are Either equipotent or more potent Than 1 a, 25 (OH) 2 D 3 in inhibiting tumor cell growth but with Fewer hypercalcemic and hypercalciuric side effects, s been Developed for the differential treatment of cancers. Recently, a pre-clinical study demonstrated That a less calcemic analog of 1 a, 25 (OH) 2 D 3, 19-nor-1 a, 25 (OH) 2 D 2 (Paricalcitol) is effective in inhibiting tumor growth in vitro and in vivo, through upregulation of p21 and p27 tumor suppressor genes. Studies on the antitumor effects of a more potent analog Paricalcitol or are underway. 1 a, 25 (OH) 2 D 3 and Its analogs are Potentially attractive novel therapies for pancreatic cancer.
© 2009 The WJG Press and Baishideng. All rights reserved.
Key words: Vitamin D, Pancreatic cancer, Calcitriol; Paricalcitol; Chemo Prevention, adenocarcinoma; CYP27b1
Peer reviewers: Dario Conte, Professor, GI Unit - IRCCS Osp. Maggiore, Chair of Gastroenterology, Via F. Sforza, 35, 20122 Milano, Italy; Ian C Roberts-Thomson, Professor, Department of Gastroenterology and Hepatology, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville South 5011, Australia
Chiang KC, Chen TC. Vitamin D for the prevention and treatment of pancreatic cancer. World J Gastroenterol 2009; 15 (27): 3349-3354 Available from: URL: http://www.wjgnet.com/1007-9327/15/3349.asp DOI: http://dx.doi.org/10.3748/wjg.15.3349
INTRODUCTION
Pancreatic adenocarcinoma is one of the must lethal human malignancies. It ranks fourth as the must common cancer-related mortality in the Western World and fifth must common worldwide [1]. There Were 37 680 new cases of pancreatic cancer and 34 290 deaths due to this disease in 2008 in the States United States States alone [2]. The overall 5-year survival rate of pancreatic cancer is estimated time to be around 1% -4%, Which is attributed to ITS aggressive growth behavior, Such As early local spread and metastasis, and resistance to radiation and must systemic chemo-therapies [1]. Also the poor prognosis is due to the Lack of effective early diagnosis. Consequently, most patiënten s been diagnosed with late-stage disease. Currently, surgery Remains the corner stone of treatment. After resection, the 5-year survival rate is 10% -29% [3-5], but only 10% -15% of pancreatic cancer patients are Suitable Candidates for resection. For the non-operable pancreatic cancer cases, the treatment must frequently Used methods include radiation and chemotherapy with 5-fluorouracil, cisplatin or gemcitabine [6-8], or a combination of theses modalities [9-11]. Growing evidence supports neoadjuvant therapy to down stage pancreatic cancer patients from some borderline resectable to resectable disease [12.13], but ITS impact on long-term survival still needs further Examination . With this bleak background, there is an urgent need to initially develop novel treatments for pancreatic cancer.
SOURCES AND METABOLISM OF VITAMIN D
The production of vitamin D 3 depends on solar ultraviolet B radiation (290-315 nm wavelength Between), Which Converts 7-dehydrocholesterol stored in the skin to previtamin D 3. Previtamin D 3 is then thermoisomerized to vitamin D 3, Which then returns entered the blood stream and is bound to the vitamin D binding protein. Very little food NaturallySpeaking contains vitamin D. The Cutaneous synthesis of vitamin D 3 normally is Responsible for about 90% of our vitamin D requirement . Vitamin D (Including Both vitamin D 2 and vitamin D 3) Obtained from dietary sources or sunlight is then Converted to 25-hydroxyvitamin D [25 (OH) D], catalyzed by vitamin D-25-hydroxylase in the liver. 25 (OH) D is the major circulating form of vitamin D and is widely accepted as an index of vitamin D status in humans. However, it is Biologically inert Until It is hydroxylated in the kidney to form a 1 ,25-dihydroxyvitamin D [1 a, 25 (OH) 2 D]. 1 a, 25 (OH) 2 D is a lipid-soluble hormone That inter acts with the vitamin D receptor (VDR) to Exert a variety of functions, include genomic and non-genomic actions.
VITAMIN D AND CANCER
1 a, 25 (OH) 2 D, the Biologically active form of vitamin D was discovered Originally ITS Because of effects on calcium and bone metabolism. It is now recognized thats the hormone HAS Activities in almost every tissue in the body. 1 a, 25 (OH) 2 D 3 implements this effect through binding to the nuclear VDR and then binding to a specific DNA sequence, the vitamin D response elements (VDRE s) . Via this genomic pathway, 1 a, 25 ( OH) 2 D 3 can-modulate gene expression in a tissue-specific marble, Mainly leading to inhibition of cellular proliferation, induction of differentiation and apoptosis, Which in turn, protect cells from malignant transformation and cancer cell growth repression.
However, the use of vitamin D to treat cancers Has Been impeded by lethal hypercalcemia induced by systemic administration or a 1, 25 (OH) 2 D 3. To over come this drawback, analogs or 1 a, 25 (OH) 2 D 3, exhibit more potent growth inhibition but less calcemic effects, have bone Developed as anti-cancer drugs , and some or themself have Shown great results in pre-clinical studies . For example, Akhter et al demonstrated That a 1 a, 25 (OH) 2 D 3 analog, EB 1089, exhibited an antiproliferative effect on colon cancer in a xenograft animal model. Abe-Hashimoto et al That showed another 1 a, 25 (OH) 2 D 3 analogue, OCT, an indication, an antitumor effect on a xenograft model Using MCF-7, a breast cancer cell line, in combination with tamoxifen. Further More, et al Polek That showed another analogue, LG190119, Possessed When Tested antiproliferative activity in an LNCaP prostate cancer cell xenograft model.
There are some limited clinical trials That show a 1, 25 (OH) 2 D 3 and Its analogs have antitumor effects in humans When Used Alone or in Combination with Other chemotherapy drugs. For example, Beer et al Conducted a clinical trial phase ‡ To Which They showed the combination of a 1, 25 (OH) 2 D 3 and docetaxel could-induce> 50% decline in PSA, a prostate cancer tumor marker, and Improve survival of prostate cancer patients. However, most of the clinical trials CONFIRMED only the less-or non-calcemic effect or a 1, 25 (OH) 2 D 3 or analog ITS When Used Alone or in Combination with Other chemotherapy drugs without ProLong the survival of cancer patients. There are still many ongoing clinical trials Attempt to Demonstrate the antitumor effect of a 1, 25 (OH) 2 D 3 and Its analogs in humans. More effort is required in order to fully appreciate the clinical utilities of vitamin D-based therapies in treating human diseases, include cancers.
MECHANISMS OF VITAMIN D FOR CANCER TREATMENT ACTIONS
Vitamin D Reduces the risk of cancer through ITS Biologically active metabolite, 1a, 25 (OH) 2 D 3, Which regulates cellular proliferation and differentiation, inhibits angiogenesis, and induces apoptosis.
Stumpf et al , in 1979, Reported That the VDR existed not only in the inte tine, bone and kidney, but in "almost all tissues in the body. Suda et al (1982) first noted a That 1, 25 (OH) 2 D 3 caused a marked inhibition of cell growth on VDR-positive M-1 leukemic cells. In The Same Year, Tanaka et al Reported That a 1, 25 (OH) 2 D 3 showed the Same effect on HL-60 leukemic cells, Which had the VDR. Since then, many cancer cell lines containing VDR, include prostate, colon, breast, lung, and melanoma, have growth inhibition Shown When Exposed to a 1, 25 (OH) 2 D 3 [15.25-27].
The antiproliferative effects of 1 a, 25 (OH) 2 D 3 are Mainly due to Alterations in Several key regulators of the cell cycle, culminating in dephosphorylation of retinoblastoma protein and cell arrest or in G 0 / G 1 417 527 795. Progression of the cell cycle is regulated by cyclin and cyclin associated Their Writers Writers kinases and cyclin kinase inhibitors (CKIs). The CKI genes, Such As p21 and / or p27, have within-VDRE Their promoter regions, and are genomic targets of the 1 a, 25 (OH) 2 D 3 / VDR complex in many cell types, Which in turn, induces G 1 cell cycle and withdrawel ruling from the cell cycle [29-31]. However, some genes are transcriptionally Affected by 1 a, 25 (OH) 2 D 3 but LACK VDREs In Their promoter regions, Which suggests That 1 a, 25 (OH) 2 D 3 induces indirect effects on cell cycle regulation through another signaling pathway. For example, 1 a, 25 (OH) 2 D 3 could-downregulate the expression of estrogen, epidermal growth factor, insulin-like growth factor 1, and keratinocyte growth factor and upregulate inhibitory growth factors, Such As transformation growth factor-b [32 -35].
1 a, 25 (OH) 2 D 3 induce differentiation can-Also to control tumor cell proliferation through the pathways of phosphatidylinositol 3-kinase, Which is VDR dependent, and by suppression of interleukin 12 protein secretion , Which is independent VDR .
Induction of apoptosis is another important function or a 1, 25 (OH) 2 D 3, Which represses the expression of the antiapoptotic protein, BCL 2, and prosurvival protein, BCL-X L. 1 a, 25 (OH) 2 D 3 Enhances Also the expression of proapoptotic proteins BAD and BAX Such As . In Addition to the BCL 2 family, 1 a, 25 (OH) 2 D 3 can-activate the caspase effector molecules directly to induce apoptosis . Further More, it Has Been Shown That a 1, 25 (OH) 2 D 3 in combination with radiation or chemo therapeutic agents, Causes an additive effect on cancer cell death [39-42].
Also inhibition of angiogenesis is an important anti-cancer mechanism or a 1, 25 (OH) 2 D 3 .1 a, 25 (OH) 2 D 3 can-representative in vitro endothelial cell growth and reducing angiogenesis in vivo [43-45]. The anti-angiogenic effects of a 1, 25 (OH) 2 D 3 Might subsequently lead to the inhibition of metastasis, as demonstrated in murine prostate and lung models Treated with a 1, 25 (OH) 2 D 3 [46.47] .
The precise anti-cancer Mechanisms of a 1, 25 (OH) 2 D 3, include VDR-dependent and VDR-independent pathways are not fully Understood. Further for the use of a 1, 25 (OH) 2 D 3 and Its analogs in the treatment of cancers, there Should Be more studies addressing this issue to pave the way for the development of a more potent 1, 25 (OH) 2 D 3 analogs.
ASSOCIATION OF VITAMIN D AND CANCER-Pancreatic Epidemiological EVIDENCE
Epidemiologic studies have Shown That vitamin D status Influenced by living at high or low latitude, solar UV exposure and dietary intake of vitamin D was inversely associated with the incidence of some cancers Such As prostate, colon and breast [48-50]. It was Also Reported That the Risk of Developing prostate, breast and colon cancer was Decreased by 30% -50% if the serum concentration or 25 (OH) D Exceeded 50 nmol / L [51.52]. Tangpricha et al That demonstrated vitamin D deficiency enhanced the growth of MC-26 colon cancer xenografts in BALB / c mice, Which supported the hypothesis That Could vitamin D sufficiency reducing the proliferation of tumor cells in vivo.
To date, there s been only two epidemiological studies Discussing the vitamin D status and the incidence of pancreatic cancer. One was Conducted by Skinner et al on U.S. nurses and health professionals, demonstrated That Which higher dietary intake of vitamin D could-be associated with lower incidence of pancreatic cancer. The other report, however, Conducted in the observational cohort of the Finnish Alpha-Beta Tocopheral Carotene (ATBC) trial, showed a Discrepancy in results compared to the report by Skinner et al . The ATBC data Suggested That a higher concentration of serum 25 (OH) D in male smokers was associated with a higher incidence of pancreatic cancer . The reason behind theses contradictory results were not clear, but They employed differential Measures of dietary intake or vitamin D versus 25 (OH) D, and the Participants in the ATBC trial Were all male smokers, Which Might have contributed to the differential in the Conclusions two studies. To Clarify this, more studies addressing the Relationship Between vitamin D status and incidence of pancreatic cancer are required.
VITAMIN D AND CANCER-Pancreatic Biochemical EVIDENCE
While the precise anti-cancer Mechanisms, Including VDR-dependent and VDR-independent actions, induced by 1 a, 25 (OH) 2 D 3-killing requirement further investigation, it is Known That in pancreatic cancer cells, 1 a, 25 (OH) 2 D 3 induces the expression of p21 and p27 and inhibits the production of cyclin (D 1, E and A) and cyclin dependent kinases 2 and 4, Which in turn, Elicit cell cycle arrest in G 0 / G 1 in vitro . Similar effects have observed leg with a 19-nor-1, 25 (OH) 2 D 2 (Paricalcitol) in human pancreatic cancer cells in vitro and in vivo by upregulate the expressions of p21 and p27 ( Figure 1 ).
Currently, very little is Known About the Mechanisms of vitamin D actions on pancreatic cancer cells. More emphasis in this area is Needed, Because very few efficient therapeutic options are available to benefit pancreatic cancer survival.
POTENTIAL FOR OR vitamin D analog Pancreatic CANCER TREATMENT
Since the VDR exists in almost every tissue of the body and -502 456 455 1 a, 25 (OH) 2 D 3 exhibits growth inhibitory effects on May differentiate types of cancer cells, bone Several studies have Performed to Investigate the anti-cancer effect of vitamin D and ITS analogs on pancreatic cancer cells consistently the Past two decades. For example, Kawa et al Reported That a 22-oxa-1, 25 (OH) 2 D 3 a 1 a, 25 (OH) 2 D 3 analog, caused growth inhibition in three pancreatic cancer cell lines and inhibited the BxPC-3 growth of a tumor in a nude mice xenograft model . Colston et al demonstrated That another 1 a, 25 (OH) 2 D 3 analog, EB 1089, exhibited more potent antitumor effects Than 1 a, 25 (OH) 2 D 3 on the CES cell line, a human pancreatic cancer cell line in vitro and in vivo. Pettersson et al Also Reported That EB 1089 induced tumor growth inhibition Greater Than 9-cis-retinoic acid in vitro. These two pre-clinical studies therefore EB 1089 Suggested That Might Be a vitamin D analog FE promising clinical trials in pancreatic cancer patients. However, in a clinical trial phase ‡ U, Which is Also the only clinical trial studying the use of vitamin D against pancreatic cancer analogs, EB 1089 Given orally once daily failed to significantly Improve patient survival, although wine Patients tolerated the daily dose orally or 10-15 m g of the drug well, without Causing hypercalcemia.
With the knowledge That 19-nor-1a, 25 (OH) 2 D 2 (Paricalcitol) is a Federal Drug Administration approved drug for the treatment and prevention of secondary hyperparathyroidism associated with chronic kidney disease , and this analog HAS comparable growth inhibitory effects as a 1, 25 (OH) 2 D 3 in human prostate cancer cells in vitro , Schwartz et al The Same analog studied in human pancreatic cancer cells in vitro and demonstrated Also thats it inhibited the proliferation of theses cells. Given the fact Paricalcitol That Has Been Shown to be less calcemic Than 1 a, 25 (OH) 2 D and few therapeutic options for pancreatic cancer patients are available, it is worth Further exploration as an anti-cancer drug for pancreatic cancer.
In Addition to Using a synthetic 1, 25 (OH) 2 D 3 analogs to treat pancreatic cancer in an effort to Avoid hypercalcemia, another strategy is the employment of inactive prohormone 25 (OH) D 3 (Figure 1). This finding is based on the normal and cancerous cells That many, include prostate cell lines and primary cultures of prostate cells, posses 25 (OH) D-1 a-hydroxylase (1-hydroxylase or a CYP27b1), the Enzyme Responsible for the conversion or 25 (OH) D 3 to 1 a, 25 (OH) 2 D 3 , and CYP27b1 Has Been Proposed as a tumor suppressor . Further More, That it Has Been demonstrated 25 (OH) D 3 had a comparable tumor growth inhibitory effect to a 1, 25 (OH) 2 D 3 on primary cultures of prostate cells [63.65]. These Findings led to a subsequent component study demo Strating That Also CYP27b1 activity was overexpressed in pancreatic cancer cells and the growth of cancer cells thesis was inhibited in the presence of 25 (OH) D 3 . Given the fact thats the conversion of 25 (OH) D 3 to 1 a, 25 (OH) 2 D 3 occure within-the-cell, and the 1 a, 25 (OH) 2 D 3 formed acts in a autocrine / paracrine fashion [ 26.63-65], systemic administration or 25 (OH) D 3 Might greatly minimize the risk of hypercalcemia. 25 (OH) D 3 Has Been Approved by the Federal Drug Administration to treat vitamin D deficiency in humans, therefore, 25 (OH) D 3 Could be another attractive candidate for clinical trials in pancreatic cancer patients.
CONCLUSION
That abundant evidence indicates a 1, 25 (OH) 2 D 3 HAS antiproliferative, pro-differentiative, apoptotic and antiangiogenic Activities in differential types or tumor cells. In differential cancer cell types, a 1, 25 (OH) 2 D 3 can-induce the expression of molecular markers to Various Artists Regulate cell growth. Same here in the tissue, cell type differentiation Might exhibit heterogeneous responses to the addition under or 1 a, 25 (OH) 2 D 3. It is Known That a 1, 25 (OH) 2 D 3 and Its can-analogs inhibit pancreatic cancer cell growth in vitro [56.59] through activation of p21 and p27, in turn Which Influence cell cycle progression in G 0 cells and Judgement / G 1. So far, only the pancreatic cancer clinical trial Using a 1 a, 25 (OH) 2 D 3 analog, EB 1089 -836 115 354, did not show significant prolongation of survival. However, a preclinical study with a 19-nor-1, 25 (OH) 2 D 2 (Paricalcitol) in pancreatic cancer cells HAS Provided Encouraging results and some Might Lead to Further clinical trials. Moreover is, Given the fact That pancreatic cancer cells posses 1 a-hydroxylase (CYP27b1) activity and can-convert the prohormone 25 (OH) D, Which Has A low risk of inducing hypercalcemia here at High Concentrations, write 1 a, 25 (OH) Within the 2 D cells and thereby inhibiting pancreatic cancer cell growth in a autocrine / paracrine fashion [26.63-65], prohormone 25 (OH) D-based therapy Might Be another attractive treatment strategy for pancreatic cancer in the future.
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