Vitamin antioxidants, lipid peroxidation and the systemic inflammatory response in patients with prostate cancer
The relationship between lipid soluble antioxidant vitamins, lipid peroxidation, disease stage and the systemic inflammatory response were examined in healthy subjects (n = 14), patients with benign prostate hyperplasia BPH (n = 20), localized (n = 40) and metastatic (n = 38) prostate cancer. Prostate cancer patients had higher concentrations of malondialdehyde (p < 0.05) and lower circulating concentrations of lutein (p < 0.05), lycopene (p < 0.001) and β-carotene (p < 0.05). Patients with metastatic prostate cancer, when compared with patients having localized disease, had a higher Gleason score (p < 0.01) and had more hormonal treatment, but lower concentrations of PSA (p < 0.05), α-tocopherol (p ≤ 0.05), retinol (p < 0.01), lutein (p < 0.05) and lycopene (p < 0.01). In the prostate cancer patients, PSA was correlated with the concentrations of the lipid peroxidation product, malondialdehyde (rs = 0.353, p = 0.002). C-reactive protein was not correlated with the vitamin antioxidants nor malondialdehyde. In contrast, there was a negative correlation between malondialdehyde concentrations and both lutein (rs = −0.263, p = 0.020) and lycopene (rs = −0.269, p = 0.017). These results indicate that lower concentrations of carotenoids, in particular, lycopene reflect disease progression rather than the systemic inflammatory response in patients with prostate cancer. © 2005 Wiley-Liss, Inc.
There is increasing evidence that systemic oxidative stress plays an important role in the development and progression of cardiovascular disease and cancer. Oxidative stress is defined as a state in which the level of toxic reactive oxygen intermediates overcomes the endogenous antioxidant defenses of the host. Oxidative stress can result, therefore, from either an excess in oxidant production or depletion of antioxidant defences.1, 2 For example, in the absence of adequate levels of lipid soluble antioxidants, this may cause functional and structural damage by reacting with lipoproteins, resulting in lipid peroxidation with the formation of degradation products such as malondialdehyde.2, 3 In particular, the carotenoid lycopene is one of the most potent antioxidants found in human plasma. However, plasma concentrations appear to better reflect prostatic exposure than self-reported usual dietary intake.4 Both the tumor growth and the systemic inflammatory response have the potential to produce reactive oxygen intermediates or oxygen free radicals and thus increase oxidative stress. Indeed, both the presence of cancer and the systemic inflammatory response are associated with lower carotenoid concentrations.5, 6, 7
It is therefore of interest that patients with prostate cancer have been reported to have low lycopene and increased oxidation of serum lipids and proteins.8 Indeed, patients with prostate cancer fed lycopene enriched supplement prior to prostatectomy appear to show reduced oxidative stress and tumor growth.9, 10, 11 However, a proportion of patients with prostate cancer will have evidence of a systemic inflammatory response,12 and its effect on lycopene concentrations is not clear.
The aim of the present study was therefore to examine the relationship between disease progression and the systemic inflammatory response and the lipid soluble antioxidant vitamins and malondialdehyde in patients with benign prostate hyperplasia (BPH), localized and metastatic prostate cancer.
Material and methods
Patients and study design
Patients with BPH (n = 20), localized (n = 40) and metastatic prostate cancer (n = 38) were studied. BPH patients were biopsy negative for prostate cancer. Metastatic prostate cancer patients had a positive bone scan. Venous blood samples were obtained for the analysis of circulating concentrations of C-reactive protein, cholesterol, vitamin A (retinol), vitamin E (α-tocopherol), carotenoids (lutein, lycopene, α- and β-carotene) and malondialdehyde. At the time of sampling, 35 of the cancer patients had not received treatment, 4 patients were scheduled for radical prostatectomy, 6 patients were scheduled for radiotherapy, 7 patients were scheduled for hormonal treatment, 8 patients were scheduled for a combination of radiotherapy and hormonal treatment and 10 patients were under watchful waiting policy.
Healthy male (nonsmoking) subjects (n = 14) were also studied as a control group. The study was approved by the local ethics committee of the North Glasgow NHS Trust.
Plasma retinol, α-tocopherol, lutein, lycopene, α-carotene and β-carotene concentrations were determined by a high-performance liquid chromatography (HPLC) method.13 Briefly, plasma was deproteinized with alcohol containing internal standards and extraction of the analytes of interest was performed using hexane. Analysis was carried out using reversed-phase HPLC (5 μm microbore, Phenomenex, Macclesfield, UK) and dual wavelength monitoring (Waters, MA). The limit of sensitivity for retinol and α-tocopherol was 0.3 and 3.0 μmol/l, respectively. The limit of sensitivity for lutein, lycopene, α-carotene and β-carotene was 10 μg/l. The intraassay coefficient of variation was less than 9% for all analytes over the sample concentration range. Where appropriate, the concentrations of the lipid soluble vitamin antioxidants were adjusted for cholesterol concentrations.
Malondialdehyde in plasma was measured as its MDA-TBA adduct, using reverse-phase high HPLC with fluorometric detection as described by Young and Trimble.14 The intraassay coefficient of variation was 9% over the sample concentration range.
Cholesterol was measured using an automated enzymatic method (Boehringer Mannheim, Mannheim, Germany). The intraassay coefficient of variation was 6% over the sample concentration range.
C-reactive protein was measured using a turbidometric assay after binding to a specific antibody on an Advia 1650 analyzer (Bayer Corporation, Tarrytown, NY). For C-reactive protein the limit of detection was 5 mg/l. The interassay coefficient of variation was less than 3 and 5% over the sample concentration range for albumin and C-reactive protein, respectively.
Total PSA was measured using the Bayer ADVIA Centaur Assay system (Bayer PLC, Bayer House, Newbury, UK). Inter-assay variability was <6% for total PSA.
Data from healthy subjects and prostatic disease groups are presented as median and range, and ANOVA (Kruskal–Wallis) was carried out. Correlations were carried out using the Spearman rank correlation. Data from different patient groups were tested for statistical significance using the Mann-Whitney U-test. Analysis was performed using SPSS software (SPSS, Chicago, IL).
The clinical characteristics, vitamin antioxidant and malondialdehyde concentrations of healthy subjects (n = 14), patients with BPH (n = 20) and prostate cancer (n = 78) are shown in Table I. Across these groups patients with prostate cancer were older (p < 0.01) had higher malondialdehyde concentrations (p < 0.05) and lower circulating concentrations of lutein (p < 0.05), lycopene (p < 0.001) and β-carotene (p < 0.05). Compared with BPH group, the prostate cancer patients had higher concentrations of PSA (p < 0.01) and malondialdehyde (p < 0.05) and lower concentrations of lycopene (p < 0.001).
Table I. Characteristics and Plasma Vitamin Antioxidant Concentrations of Controls, Patients With BPH and Prostate Cancer
|Age (yr)||64 (45–83)1||67 (45–85)||70 (49–93)||0.005|
|Gleason score|| || ||6 (2–10)|| |
|PSA (ng/ml)|| ||1.5 (0.2–12.3)||6.2 (0.1–840)||0.001|
|≤10/>10 ng/ml|| ||19/1||44/34||0.001|
|C-reactive protein (mg/l)||<5 (<5–12)||<5 (<5–21)||<5 (<5–100)||0.094|
|Cholesterol (mmol/l)||5.6 (4.5–7.7)||5.0 (2.0–7.3)||5.3 (3.4–7.3)||0.321|
|Malondialdehyde (μmol/l)||0.73 (0.50–1.40)||0.74 (0.35–1.48)||0.93 (0.44–4.67)||0.012|
|Retinol (μmol/l)||1.8 (1.2–1.6)||1.9 (1.2–3.0)||2.0 (0.7–4.9)||0.248|
|α-Tocopherol (μmol/l)||27.0 (19.0–45.0)||27.0 (18.0–39.0)||25.0 (11.0–63.0)||0.267|
|Lutein (μg/l)||121 (48–235)||99 (55–151)||88 (14–252)||0.046|
|Lycopene (μg/l)||127 (17–320)||128 (18–223)||59 (<10–687)||<0.001|
|α-Carotene (μg/l)||33.5 (11–68)||15.5 (<10–45.0)||23.0 (<10–134)||0.057|
|β-Carotene (μg/l)||163 (25–358)||62 (<10–289)||86 (<10–381)||0.013|
|Treatment (none/hormonal)|| || ||35/43|| |
The clinical characteristics, vitamin antioxidant and malondialdehyde concentrations of patients with localized (n = 40) and metastatic (n = 38) prostate cancer are shown in Table II. Patients with metastatic prostate cancer had a higher Gleason score (p < 0.01), but lower concentrations of PSA (p < 0.05), α-tocopherol (p ≤ 0.05), retinol (p < 0.01), lutein (p < 0.05) and lycopene (p < 0.01). Compared with localized disease there was more hormonal treatment in the metastatic group (p < 0.001).
Table II. Characteristics and Plasma Vitamin Antioxidant Concentrations of Patients With Localized and Metastatic Prostate Cancer
|Age (yr)||70 (49–93)1||74 (51–92)||0.209|
|Gleason score||5 (2–8)||7 (2–10)||0.001|
|PSA (ng/ml)||11.6 (0.1–58.2)||2.8 (0.1–840)||0.091|
|C-reactive protein (mg/l)||<5 (<5–63)||<5 (<5–100)||0.135|
|Cholesterol (mmol/l)||5.5 (3.4–7.3)||5.2 (3.7–7.0)||0.802|
|Malondialdehyde (μmol/l)||0.93 (0.47–2.93)||1.01 (0.44–4.67)||0.490|
|Retinol (μmol/l)||2.2 (1.1–4.9)||1.9 (0.7–3.2)||0.008|
|α-Tocopherol (μmol/l)||26.0 (16.0–63.0)||22.5 (11.0–45.0)||0.051|
|Lutein (μg/l)||103 (31–252)||76 (14–240)||0.024|
|Lycopene (μg/l)||83 (14–687)||42 (<10–226)||0.001|
|α-Carotene (μg/l)||27.0 (<10–134)||19.5 (<10–125)||0.130|
|β-carotene (μg/l)||96 (14–381)||60 (<10–281)||0.067|
In the prostate cancer patients, PSA was not correlated with the vitamin antioxidants, but was correlated with the concentrations of the lipid peroxidation product, malondialdehyde (rs = 0.353, p =0.002). C-reactive protein was not correlated with the vitamin antioxidants nor malondialdehyde. In contrast, there was a negative correlation between malondialdehyde concentrations and both lutein (rs = −0.263, p = 0.020) and lycopene (rs = −0.269, p = 0.017).
In the present study, there was a lowering of lutein and lycopene concentrations, by approximately 40 and 70%, respectively, from normal subjects and patients with BPH to patients with localized prostate cancer and to patients with metastatic prostate cancer. In contrast, malondialdehyde concentrations increased by approximately 25% from normal subjects and patients with BPH to patients with localized or metastatic prostate cancer. These results would suggest that lower carotenoid concentrations are associated with the progression of the disease to metastases, whereas higher lipid peroxidation is primarily associated with the presence of cancer. However, since the numbers of patients receiving hormonal treatment, at the time of sampling, was higher in patients with metastatic disease compared with those with localized prostate cancer, we can not discount the possibility that treatment influenced lutein and lycopene concentrations in these patients. Indeed, it is likely that hormone treatment resulted in the low PSA concentrations in the metastatic group. It is also not clear from the present cross sectional study whether low lycopene concentrations play a role in the progression of prostate cancer9, 10, 11 or merely a result of disease activity or diet.
In the present study, there was no significant association between C-reactive protein and the lipid soluble vitamin antioxidants in the prostate cancer patients. With respect to the previously reported inverse relationship between C-reactive protein concentrations and such lipid soluble vitamin antioxidants concentrations, the results of the present study appear contradictory.5, 7 However, in the present study the prostate cancer patients had a median C-reactive protein concentration of less than 5mg/l compared with approximately 40mg/l in lung cancer patients5 and 70mg/l in patients with colorectal cancer.7
It was of interest that, in the present study, patients with localized prostate cancer had higher retinol concentrations compared with either the BPH or metastatic groups. The reasons for this difference are unclear. However, this may reflect the conversion of some carotenoids to vitamin A in early stage disease.
In summary, the results of the present study indicate that lower concentrations of carotenoids, in particular, lycopene reflect disease progression rather than the systemic inflammatory response in patients with prostate cancer.