Chinese Medical Journal 2014;127(11):2143-2146:10.3760/cma.j.issn.0366-6999.20132829
Lycopene can reduce prostate-specific antigen velocity in a phase II clinical study in Chinese population

Zhang Xin, Yang Yong and Wang Qi

Keywords
lycopene; prostate-specific antigen; prostate cancer
Abstract
Background Epidemiological studies have shown that lycopene has anti-prostate cancer effect. In vitro tests also confirmed that it can promote apoptosis of prostate cancer cells. We investigated the effect of whole-tomato supplement lycopene on the prostate-specific antigen velocity in selected prostate cancer patients.
Methods Twenty selected prostate cancer patients were given whole-tomato supplement lycopene 10 mg per day for about 6 months. Blood samples of patients were collected weekly to measure serum prostate-specific antigen (PSA) values. PSA velocity slope, which reflects the change of PSA, and the degree of change were also calculated. By comparing the values of average PSA velocity slope (rise or fall of PSA) before and after the administration of lycopene, the effect of lycopene can be evaluated. Blood chemistry analysis was regular followed as safety control.
Results Three patients in the research group withdrew within 3 weeks because of inability to conform. The rest 17 patients continued for an average period of 6 months. Two patients withdrew because of cancer progression (PSA rise) who later received active treatment. The average fall in PSA was equivalent to 2.56% over (i.e. an average slope/d of −0.000 28) the first 3 months. In the last 3 months, average fall in PSA was equivalent to 31.58% (i.e. an average slope/d of −0.003 51). The Wilcoxon rank-sum test showed a statistically significant decrease of PSA velocity slope overall (P=0.000 9). Analysis of the PSA doubling time (pre- vs. post-treatment) showed a median increase over 3 months but this was not statistically significant (P=0.21). No toxic side effect was observed during the whole process. The results indicate that the average PSA change is “decline” in patients, and the degree of the decline is accelerated.
Conclusion Administration of lycopene was able to reduce PSA velocity in this study group.
Lycopene is afamily member of carotenoid, which mainly exists in fruits, especially in tomato. In recent years, lycopene has been in focus because of its mysterious role in the prevention and treatment of cancer.1,2Previous epidemiological research found lycopene intake had an inverse relationship with prostate cancer morbidity.3,4Primary research revealed the function of lycopene as a strong anti-oxidant dietary factor that can prevent cellular protein and lipids damage, which in turn interfere with cancer evolution.5,6Later research found that lycopene can inhibit cell proliferation and DNA synthesis in prostate cancer cell lines, like PC3, DU145, LnCaP etc.7-10The results were not convincing enough, for thein vitrocell lines may not reflect the real prostate character. Hence, our research group isolated the primary prostate epithelial cells and for the first time reported that lycopene can inhibit cell proliferation and DNA synthesis in the primary prostate epithelial cells.11Moreover, we recently used luciferase report gene and found that lycopene can inhibit androgen receptor element gene activity and expression, which revealed further function point of lycopene.12We offered lycopene tablets to selected prostate cancer patients who were temporarily free from active treatment and whose prostate-specific antigen (PSA) was stable and tried to find whether lycopene can help them more.
METHODS
Study design
The aim of this study was to confirm whether lycopene supplement can alter the PSA velocity (rise or fall of serum PSA). If PSA velocity post-administration occurred compared with before, it was defined as response.
Patient selection
Between August 2011 and July 2012, 20 patients with pathologically diagnosed prostate cancer were enrolled in this study. Patients who were eligible for inclusion were 60 to 85 years old with stable PSA for the recent 3 months, whatever the value. Exclusion criteria included: (1) recent 3 months without any other active treatment for the disease, including hormone therapy or radiotherapy, which will cause PSA value fluctuation; (2) patients should not have ever received lycopene or other carotenoids supplement before through questionnaires; (3) people who are allergic to tomato products; (4) prostate cancer of patients is high risk and significant progress (Gleason ≥8, PSA >20 ng/ml);
(5) severe co-morbidity in patients not compatible with lycopene supplement therapy, such as new myocardial infarction, unstable angina or cerebrovascular accident in recent 6 months; and (6) patients involved in other trials that may influence the results.
Patients withdraw criteria
Patients’ inability to conform to the study protocol, rapid tumor progression and other adverse events were considered as withdraw criteria.
This study protocol was approved by the ethics committee of Peking University Cancer Hospital & Institute. All patients enrolled had signed informed consent before participating in the study.
Treatment
Before this study, patients enrolled had received other treatment for their disease, such as anti-androgen therapy, surgery, external radiotherapy or active surveillance. Patients were divided into four groups to follow up the results according to the original treatment. All the patients would receive treatment of lycopene product 10 mg lycopene per day supplement (oral capsule package, each capsule contained 5 mg lycopene, donated by Hergestellt fur George & Partners Ltd., Newcastle, England) after dinner. During treatment, all patients were required to record the type and quantity of food daily, to maintain a stable diet as much as possible, and try to avoid a large, long-term intake of tomato-based foods. All patients were recorded for allergic or toxic reactions. By lycopene supply treatment for at least 6 months, changes were observed for PSA and PSA velocity in each patient group, and in all the patients.
During the study, if patients had significant lycopene allergy or poisoning, they were immediately withdrawn from the study, given the appropriate rescue and treatment, and the reasons were analyzed. Also, if the progression of prostate cancer, such as significant increase in PSA, happens, patients were withdrawn from the study immediately and subjected to further strengthening treatment.
Follow up
PSA is a protein produced by cells of the prostate gland. Serum PSA test is used to monitor cancer recurrence in prostate cancer patients. Patients in this study were required to follow up weekly at urology clinic to check for any side effect, collect venous blood, obtain the value of serum PSA, and check liver and kidney functions. It is to record the changes in serum PSA and PSA velocity as well as to study the basic health condition of the patient, to ensure safety of the study.
Statistical analysis
Linear regression was used to calculate andcompare average PSA velocity before and after administration. A repaired Wilcoxon sign-rank test was used to compare slopes of log PSA against time in patients pre- and post-treatment. Based on these slopes, pre and post-treatment PSA doubling times were calculated as log2/slope.
RESULTS
Patient characteristics
From 1st August 2011 to 31st July 2012, we enrolled 20 patients who were diagnosed of prostate cancer and had received different treatments before (Table 1), average age was (72±7) years, average PSA at diagnosis was (22.7±4.2) ng/ml, average Gleason Score was 7. They have received different treatments including anti-androgen therapy, external beam radiotherapy, surgery or active surveillance. Three patients in the research group withdrew within 3 weeks because of inability to conform. The rest 17 patients continued with lycopene supplement for an average period of 6 months. They were closely followed up for serum PSA level and adverse event (Figure 1). Before the study, average PSA was (5.7±0.8) ng/ml. At the beginning of study, two more patients withdrew because of cancer progression (PSA rise), who later received active treatment. No significant toxicity was observed.
Effectiveness and safety analysis
In this study, a decrease in PSA velocity was found in the treatment group, regarded as effectiveness of lycopene (Figure 2). PSA is a kind of specific protein produced by prostate epithelial cell. in prostate cancer patients, the change in PSA values reflects the progression of the disease. The level of activity of cancer in a patient can be assessed by continuous measurement of PSA values. PSA velocity reflect PSA trend, and PSA velocity slope calculated during the study period can show the overall change in serum PSA and may predict the trend of PSA. We conclude that lycopene has the ability to delay tumor progression.
To ensure the safety of all the patients enrolled in the study, we took blood samples monthly, to monitor CBC, AST, ALT, and creatine. We recorded any adverse events for each patient to early detect any side effect of lycopene. During the whole study period, the laboratory tests of all the patients were considered within safety range and we got no significant adverse events. We clear that lycopene as a tomato extract is safe for people.
PSA data analysis
Regression slope of (log) PSA vs. time decreased in 15 of 17 (88%, 95%CI69%–93%) patients after supplementation. The average fall in PSA was equivalent to 2.56% over the first 3 months (i.e. an average slope/d of-0.000 28). In the last 3 months average fall in PSA was equivalent to 31.58% (i.e. an average slope/d of -0.003 51).
The Wilcoxon rank-sum test showed a statistically significant decrease of PSA velocity in slope overall (P=0.000 9). The result shows an increase in PSA velocity slope, and the slope is negative. It indicates that the average PSA change is “decline” in patients, and the degree of the decline is accelerated. Analysis of the PSA doubling time (pre vs. post-treatment) showed a median increase over 3 months but this was not statistically significant (P=0.21, Figure 2). No toxic side effect was observed during the whole process.
DISCUSSION
Prostate cancer has always been the focus of both clinical and laboratory research. Population who migrated from low-risk countries, such as Japan and Poland, to high-risk countries, such as USA, have an increased risk of developing the disease.13Our research ruled out the possibility that differences in diagnosis led to this result. Researchers later found diet difference may be responsible for that and that provoked numerous studies on the relation between dietary factors and prostate cancer.14-17The oxidative damage of cellular protein, lipid, and DNA has long been regarded as a possible mechanism of the development of cancer.18Lycopene, which belongs to the family of carotenoids, is a significant anti-oxidant and may provide protection of DNA and membrane lipids from oxidative damage; it is not surprising that there has been a lot of interest on its chemoprevention effect on cancer.
Many previous studies using currently available cell lines like PC3, DU145, LnCaP established that lycopene can inhibit DNA synthesis and cell proliferation of these prostate cancer cell lines.19There were also doubts that those cell lines can not really reflect the conditionin vivo.20Thus we used more reliable prostate primary epithelial cells and for the first time showed that lycopene can also inhibit normal prostate epithelial cell growth.21This made us move forward to study the function theory. Our latest research revealed that lycopene can inhibit androgen receptor element gene expression and translation in a dose-related manner, which also highlights the treatment for hormone refractory prostate cancer.
Based on the above research, we carried out the clinical study of the impact of lycopene on prostate cancer patients. Considering it would be impractical to expect lycopene only, just as one kind of dietary factor to control the prostate cancer progression, here we use log PSA for evaluation. The clinical study here reinforces the positive findings of the previous trials and demonstrates an ongoing and real effect upon serum PSA, and therefore possibly on the behavior of established CaP in patients receiving no other form of treatment. Indeed, while the overall effect was to demonstrate a statistical shallowing of the gradient of PSA, there was also a large increase in the estimated PSA doubling time. However, this increase did not reach statistical significance.
The result of this study supports the discussion whole-tomato lycopene might slow disease progression in men with prostate cancer. As a nutrient, lycopene is widespread in people's food. It is non-toxic, has no side effects, and is easy to obtain and accepted. Its therapeutic effect on prostate cancer is worth the attention of nutritionists and oncologists. We also need to be aware that variations in base-line dietary habits are not included, although patients taking either supplements or extra tomatoes were not recruited. In the present study, the number of patients was limited. In addition, because the study was not a randomized controlled study, there was some bias.
This pilot study confirms the effect of lycopene on the treatment of prostate cancer patients, but further and large randomized studies are still needed in near future.
REFERENCES
(Received November 5, 2013)
Edited by Sun Jing
DOI: 10.3760/cma.j.issn.0366-6999.20132829
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Urology, Peking University Cancer Hospital & Institute, Beijing 100020, China (Zhang X and Yang Y)
Department of Urology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China (Wang Q)
Correspondence to: Dr. Wang Qi, Department of Urology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China (Tel: 86-10-83198460. Fax: 86-10-83198388. Email: wangqi6@medmail.com.cn)
This study was sponsored by the grant from Beijing Municipal Science and Technology Committee (No. 2004B-01).
Table 1.Patient information
Items External beam radiotherapy Active surveillance Anti-androgen therapy Surgery
Number (n) 2 5 9 4
Age (years) 77±2 65±4 74±4 69±4
Gleason score 7.0±0.2 6.0±0.7 7.0±1.3 6.0±0.5
Time since diagnosis (years) 1.9±0.8 2.3±0.4 2.2±0.2 1.5±0.7
PSA (ng/ml) 18.7±5.8 7.9±1.3 29.7±9.1 15.5±4.7

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Figure 1. Flow chart of patient enrolment into this study.

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Figure 2. LogPSA shows the results of PSA of patients at weekly inspections. Week 0 indicates LogPSA value before the study. Weeks 4 to 32 indicate LogPSA values during the study. Linear regression shows that LogPSA decreased with time. Connecting curve shows that LogPSA decreased with time.