Correspondence
submission (Table 1). Therefore, delays in approval between the FDA and HC include discrepancies in both submission dates and the length of regulatory review time. We concur with Wilson et al that streamlining the drug approval process by centralizing drug submission across multiple regulatory agencies is an ideal starting point in alleviating delays in drug approval. This mechanism could potentially be empowered to add international consistency to drug approval indications. Hopefully, the cost of a centralized submission would be made reasonable for smaller drug companies. In the interim, encouraging larger drug companies to submit simultaneously to multiple regulatory agencies and decreasing regulatory review times are potential ways to accelerate access to new oncology therapies for our patients. FUNDING SUPPORT No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.
REFERENCE 1. Ezeife DA, Truong TH, Heng DY, Bourque S, Welch SA, Tang PA. Comparison of oncology drug approval between Health Canada and the US Food and Drug Administration. Cancer. 2015;121:1688-1693.
Doreen A. Ezeife, MD Department of Medicine University of Calgary Calgary, Alberta, Canada
Tony H. Truong, MD Section of Pediatric Oncology Department of Oncology University of Calgary Calgary, Alberta, Canada
Patricia A. Tang, MD Department of Oncology Tom Baker Cancer Centre Calgary, Alberta, Canada DOI: 10.1002/cncr.29482, Published online June 16, 2015 in Wiley Online Library (wileyonlinelibrary.com)
Investigating the Relationship Between Vitamin D and Cancer Requires Dosing the Bioavailable Nonhydroxylated Vitamin D Storage in Cancer Tissues In a recent article published in Cancer, Shui et al observed no statistically significant relationship between circulating 25-hydroxyvitamin D (25(OH)D) and fatal prostate can3362
cer (PCa).1 However, an association between cytochrome P450 2R1 (CYP2R1) single-nucleotide polymorphisms (SNPs) and fatal PCa was found.1 CYP2R1 is the hydroxylase involved in the conversion of vitamin D into 25(OH)D. In the classic vitamin D endocrine system, the activation of vitamin D into 1,25(OH)2D requires 2 successive hydroxylation steps. The first is catalyzed by CYP2R1 in the liver and the second by CYP27B1 in the kidneys. Then, 1,25D is released in the blood circulation and behaves as an endocrine hormone. The conversion of 25(OH)D into the active hormone 1,25(OH)2D by CYP27B1 is under stringent control. However, the first hydroxylation step catalyzed in the liver by CYP2R1 is constitutive and is not believed to be subjected to tight regulation. This has 2 important consequences: 1) the regulation of liver CYP2R1 has retained little attention; and 2) circulating nonhydroxylated vitamin D is rapidly metabolized by liver CYP2R1. Therefore, 25(OH)D concentrations are considered to reflect vitamin D inputs and are used to determine the vitamin D status of the patient. A major breakthrough in our understanding of the nonskeletal effects of vitamin D is the recent discovery of autocrine/paracrine vitamin D systems in many tissues.2 This autocrine/paracrine signaling ensures the local bioactivation of 25(OH)D into 1,25(OH)2D by extrarenal CYP27B1. In autocrine/paracrine vitamin D systems, the vitamin D metabolites are produced, act, and are degraded locally without affecting serum 25(OH)D levels. Shui et al rightly pointed out that local synthesis of 1,25(OH)2D from 25(OH)D can occur because CYP27B1 is expressed in the prostate. However, the authors do not mention that CYP2R1 is also expressed in prostate tissue.3 The fact that the prostate can also perform the conversion of vitamin D into 25(OH)D is critical. The activity of prostate CYP2R1 depends on the local bioavailability of its substrate, namely nonhydroxylated vitamin D. There is very little circulating nonhydroxylated vitamin D in the body, but storage can occur. This requires large inputs and is mainly observed in fat tissues when circulating 25(OH)D concentrations exceed 90 nmol/L.4 This value is higher than the defined physiological levels for 25(OH)D sufficiency (50 nmol/ L-75 nmol/L), but is consistent with 25(OH)D concentrations suggested to reduce cancer risk (approximately 150 nmol/L).5 The existence of a functional vitamin D autocrine/paracrine system in the prostate that depends on the local bioavailability of nonhydroxylated vitamin D explains the findings reported by Shui et al1: 1) the lack of a significant association between circulating 25(OH)D Cancer
September 15, 2015
Correspondence
and fatal PCa; and 2) the association between CYP2R1 SNPs and fatal PCa. Expression of CYP2R1 and CYP27B1 is regulated by inflammatory stimuli.6 In the prostate cancer inflammatory microenvironment, locally bioavailable nonhydroxylated vitamin D would be metabolized first by prostate CYP2R1 to generate 25(OH)D and then by CYP27B1 to produce 1,25(OH)D. This prostate autocrine/paracrine vitamin D system is disconnected to the physiological circulating levels of 25(OH)D (50 nmol/L-75 nmol/L) but will depend on local stores of nonhydroxylated vitamin D and of CYP2R1 activity. The coexistence of 2 vitamin D systems (endocrine and autocrine/paracrine) with different aims and characteristics, including optimal vitamin D requirements, sheds light on the complexity of the vitamin D functions. The association between CYP2R1 SNPs and fatal PCa described by Shui et al1 points to the importance of including analyses regarding the bioavailability of nonhydroxylated vitamin D in studies investigating relationships between vitamin D and cancer. FUNDING SUPPORT No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.
REFERENCES 1. Shui IM, Mondul AM, Lindstrom S, et al; for the Breast and Prostate Cancer Cohort Consortium Group. Circulating vitamin D, vitamin D-related genetic variation, and risk of fatal prostate cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium [published online ahead of print March 2, 2015]. Cancer. doi:10.1002/cncr.29320. 2. Feldman D, Krishnan AV, Swami S, Giovannucci E, Feldman BJ. The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer. 2014;14:342-357. 3. Chen TC, Sakaki T, Yamamoto K, Kittaka A. The roles of cytochrome P450 enzymes in prostate cancer development and treatment. Anticancer Res. 2012;32:291-298. 4. Heaney RP, Armas LA, Shary JR, Bell NH, Binkley N, Hollis BW. 25-Hydroxylation of vitamin D3: relation to circulating vitamin D3 under various input conditions. Am J Clin Nutr. 2008;87:1738-1742. 5. Garland CF, French CB, Baggerly LL, Heaney RP. Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention. Anticancer Res. 2011;31:607-611. 6. El-Atifi M, Dreyfus M, Berger F, Wion D. Expression of CYP2R1 and VDR in human brain pericytes: the neurovascular vitamin D autocrine/paracrine model. Neuroreport. 2015;26:245-248.
Matthieu Dreyfus Didier Wion, PhD INSERM UA01, Clinatec, Edmond J. Safra Biomedical Research Center CEA Grenoble, France
DOI: 10.1002/cncr.29451, Published online May 19, 2015 in Wiley Online Library (wileyonlinelibrary.com)
Cancer
September 15, 2015
Reply to Investigating the Relationship Between Vitamin D and Cancer Requires Dosing the Bioavailable Nonhydroxylated Vitamin D Storage in Cancer Tissues We read with interest the letter from Drs. Dryfus and Wion. The longstanding endocrine paradigm for vitamin D activity is defined by a 2-step hydroxylation process in which vitamin D precursors from diet and sunlight are metabolized in the liver to the major circulating form of 25-hydroxyvitamin D (25(OH)D) and then in the kidney to the active form calcitriol (1,25(OH)2D). Calcitriol then acts as a steroid hormone and regulates cellular functions through binding to the vitamin D receptor. The conversion to calcitriol in the kidney is heavily regulated by calcium homeostasis. The hypothesis of Drs. Dryfus and Wion is predicated on the more newly discovered tissue-specific autocrine/paracrine paradigm for vitamin D activity, in which vitamin D precursors are directly converted to 25(OH)D and calcitriol in target tissues, including the prostate. In our study of circulating 25(OH)D and common genetic variants of the vitamin D pathway, we observed that variation in cytochrome P450 2R1 (CYP2R1) was associated with the risk of fatal prostate cancer only among men with low circulating 25(OH)D.1 The risk of fatal prostate cancer was found to be highest in those men, who despite carrying CYP2R1 alleles that are associated with higher levels of 25(OH)D in the general population, still had low circulating 25(OH)D. CYP2R1 is a cytochrome P450 enzyme that is responsible for the primary hydroxylation step in the resulting in 25(OH)D. Having low circulating 25(OH)D despite being genetically predisposed to higher levels may indicate that these men have particularly low supplies of nonhydroxylated vitamin D (eg, from diet or sun exposure). Drs. Dryfus and Wion propose an explanation for our findings that are in line with the autocrine/paracrine paradigm, namely that variation in CYP2R1 affects prostate production of 25(OH)D from local stores of bioavailable nonhydroxylated vitamin D. Although CYP27B1, the 1-alpha-hydroxylase that catalyzes the conversion of 25(OH)D to calcitriol, has been more widely studied, CYP2R1 recently was shown to be the main functional 25-hydroxylase expressed in prostate 3363
submission (Table 1). Therefore, delays in approval between the FDA and HC include discrepancies in both submission dates and the length of regulatory review time. We concur with Wilson et al that streamlining the drug approval process by centralizing drug submission across multiple regulatory agencies is an ideal starting point in alleviating delays in drug approval. This mechanism could potentially be empowered to add international consistency to drug approval indications. Hopefully, the cost of a centralized submission would be made reasonable for smaller drug companies. In the interim, encouraging larger drug companies to submit simultaneously to multiple regulatory agencies and decreasing regulatory review times are potential ways to accelerate access to new oncology therapies for our patients. FUNDING SUPPORT No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.
REFERENCE 1. Ezeife DA, Truong TH, Heng DY, Bourque S, Welch SA, Tang PA. Comparison of oncology drug approval between Health Canada and the US Food and Drug Administration. Cancer. 2015;121:1688-1693.
Doreen A. Ezeife, MD Department of Medicine University of Calgary Calgary, Alberta, Canada
Tony H. Truong, MD Section of Pediatric Oncology Department of Oncology University of Calgary Calgary, Alberta, Canada
Patricia A. Tang, MD Department of Oncology Tom Baker Cancer Centre Calgary, Alberta, Canada DOI: 10.1002/cncr.29482, Published online June 16, 2015 in Wiley Online Library (wileyonlinelibrary.com)
Investigating the Relationship Between Vitamin D and Cancer Requires Dosing the Bioavailable Nonhydroxylated Vitamin D Storage in Cancer Tissues In a recent article published in Cancer, Shui et al observed no statistically significant relationship between circulating 25-hydroxyvitamin D (25(OH)D) and fatal prostate can3362
cer (PCa).1 However, an association between cytochrome P450 2R1 (CYP2R1) single-nucleotide polymorphisms (SNPs) and fatal PCa was found.1 CYP2R1 is the hydroxylase involved in the conversion of vitamin D into 25(OH)D. In the classic vitamin D endocrine system, the activation of vitamin D into 1,25(OH)2D requires 2 successive hydroxylation steps. The first is catalyzed by CYP2R1 in the liver and the second by CYP27B1 in the kidneys. Then, 1,25D is released in the blood circulation and behaves as an endocrine hormone. The conversion of 25(OH)D into the active hormone 1,25(OH)2D by CYP27B1 is under stringent control. However, the first hydroxylation step catalyzed in the liver by CYP2R1 is constitutive and is not believed to be subjected to tight regulation. This has 2 important consequences: 1) the regulation of liver CYP2R1 has retained little attention; and 2) circulating nonhydroxylated vitamin D is rapidly metabolized by liver CYP2R1. Therefore, 25(OH)D concentrations are considered to reflect vitamin D inputs and are used to determine the vitamin D status of the patient. A major breakthrough in our understanding of the nonskeletal effects of vitamin D is the recent discovery of autocrine/paracrine vitamin D systems in many tissues.2 This autocrine/paracrine signaling ensures the local bioactivation of 25(OH)D into 1,25(OH)2D by extrarenal CYP27B1. In autocrine/paracrine vitamin D systems, the vitamin D metabolites are produced, act, and are degraded locally without affecting serum 25(OH)D levels. Shui et al rightly pointed out that local synthesis of 1,25(OH)2D from 25(OH)D can occur because CYP27B1 is expressed in the prostate. However, the authors do not mention that CYP2R1 is also expressed in prostate tissue.3 The fact that the prostate can also perform the conversion of vitamin D into 25(OH)D is critical. The activity of prostate CYP2R1 depends on the local bioavailability of its substrate, namely nonhydroxylated vitamin D. There is very little circulating nonhydroxylated vitamin D in the body, but storage can occur. This requires large inputs and is mainly observed in fat tissues when circulating 25(OH)D concentrations exceed 90 nmol/L.4 This value is higher than the defined physiological levels for 25(OH)D sufficiency (50 nmol/ L-75 nmol/L), but is consistent with 25(OH)D concentrations suggested to reduce cancer risk (approximately 150 nmol/L).5 The existence of a functional vitamin D autocrine/paracrine system in the prostate that depends on the local bioavailability of nonhydroxylated vitamin D explains the findings reported by Shui et al1: 1) the lack of a significant association between circulating 25(OH)D Cancer
September 15, 2015
Correspondence
and fatal PCa; and 2) the association between CYP2R1 SNPs and fatal PCa. Expression of CYP2R1 and CYP27B1 is regulated by inflammatory stimuli.6 In the prostate cancer inflammatory microenvironment, locally bioavailable nonhydroxylated vitamin D would be metabolized first by prostate CYP2R1 to generate 25(OH)D and then by CYP27B1 to produce 1,25(OH)D. This prostate autocrine/paracrine vitamin D system is disconnected to the physiological circulating levels of 25(OH)D (50 nmol/L-75 nmol/L) but will depend on local stores of nonhydroxylated vitamin D and of CYP2R1 activity. The coexistence of 2 vitamin D systems (endocrine and autocrine/paracrine) with different aims and characteristics, including optimal vitamin D requirements, sheds light on the complexity of the vitamin D functions. The association between CYP2R1 SNPs and fatal PCa described by Shui et al1 points to the importance of including analyses regarding the bioavailability of nonhydroxylated vitamin D in studies investigating relationships between vitamin D and cancer. FUNDING SUPPORT No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.
REFERENCES 1. Shui IM, Mondul AM, Lindstrom S, et al; for the Breast and Prostate Cancer Cohort Consortium Group. Circulating vitamin D, vitamin D-related genetic variation, and risk of fatal prostate cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium [published online ahead of print March 2, 2015]. Cancer. doi:10.1002/cncr.29320. 2. Feldman D, Krishnan AV, Swami S, Giovannucci E, Feldman BJ. The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer. 2014;14:342-357. 3. Chen TC, Sakaki T, Yamamoto K, Kittaka A. The roles of cytochrome P450 enzymes in prostate cancer development and treatment. Anticancer Res. 2012;32:291-298. 4. Heaney RP, Armas LA, Shary JR, Bell NH, Binkley N, Hollis BW. 25-Hydroxylation of vitamin D3: relation to circulating vitamin D3 under various input conditions. Am J Clin Nutr. 2008;87:1738-1742. 5. Garland CF, French CB, Baggerly LL, Heaney RP. Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention. Anticancer Res. 2011;31:607-611. 6. El-Atifi M, Dreyfus M, Berger F, Wion D. Expression of CYP2R1 and VDR in human brain pericytes: the neurovascular vitamin D autocrine/paracrine model. Neuroreport. 2015;26:245-248.
Matthieu Dreyfus Didier Wion, PhD INSERM UA01, Clinatec, Edmond J. Safra Biomedical Research Center CEA Grenoble, France
DOI: 10.1002/cncr.29451, Published online May 19, 2015 in Wiley Online Library (wileyonlinelibrary.com)
Cancer
September 15, 2015
Reply to Investigating the Relationship Between Vitamin D and Cancer Requires Dosing the Bioavailable Nonhydroxylated Vitamin D Storage in Cancer Tissues We read with interest the letter from Drs. Dryfus and Wion. The longstanding endocrine paradigm for vitamin D activity is defined by a 2-step hydroxylation process in which vitamin D precursors from diet and sunlight are metabolized in the liver to the major circulating form of 25-hydroxyvitamin D (25(OH)D) and then in the kidney to the active form calcitriol (1,25(OH)2D). Calcitriol then acts as a steroid hormone and regulates cellular functions through binding to the vitamin D receptor. The conversion to calcitriol in the kidney is heavily regulated by calcium homeostasis. The hypothesis of Drs. Dryfus and Wion is predicated on the more newly discovered tissue-specific autocrine/paracrine paradigm for vitamin D activity, in which vitamin D precursors are directly converted to 25(OH)D and calcitriol in target tissues, including the prostate. In our study of circulating 25(OH)D and common genetic variants of the vitamin D pathway, we observed that variation in cytochrome P450 2R1 (CYP2R1) was associated with the risk of fatal prostate cancer only among men with low circulating 25(OH)D.1 The risk of fatal prostate cancer was found to be highest in those men, who despite carrying CYP2R1 alleles that are associated with higher levels of 25(OH)D in the general population, still had low circulating 25(OH)D. CYP2R1 is a cytochrome P450 enzyme that is responsible for the primary hydroxylation step in the resulting in 25(OH)D. Having low circulating 25(OH)D despite being genetically predisposed to higher levels may indicate that these men have particularly low supplies of nonhydroxylated vitamin D (eg, from diet or sun exposure). Drs. Dryfus and Wion propose an explanation for our findings that are in line with the autocrine/paracrine paradigm, namely that variation in CYP2R1 affects prostate production of 25(OH)D from local stores of bioavailable nonhydroxylated vitamin D. Although CYP27B1, the 1-alpha-hydroxylase that catalyzes the conversion of 25(OH)D to calcitriol, has been more widely studied, CYP2R1 recently was shown to be the main functional 25-hydroxylase expressed in prostate 3363
