Based on prior work demonstrating that dietary lycopene provided from a whole tomato product (tomato powder) inhibited carcinogenesis to a greater degree than lycopene beadlet in an NMU-testosterone treated rat model, we hypothesized that TP but not LB would inhibit carcinogenesis in TRAMP mice. On the contrary in the present study, TRAMP mice in the LB group had a reduced incidence of prostate cancer relative to the control group whereas the difference in prostate cancer incidence between the TP and control group was not significant. The reasons for these disparate findings are unclear. Analysis of serum levels of IGF-I, IGFBP-3, prostate tissue levels of lycopene, and oxidative DNA damage in the liver demonstrated no significant difference between mice fed TP and mice fed LB. In addition, there was no difference in lycopene levels in the TP and LB feed pellets and no difference in lycopene content deterioration in the pellets over time. Given the known deterioration of lycopene that can occur with exposure to air and light, feeding experiments that incorporate lycopene should document lycopene levels in the experimental diets and deterioration over time.
One difference between the tomato powder preparation used by Boileau, et al. and the paste used in the present trial was that the tomato powder contained the skin and seeds of the tomato, whereas the tomato paste used in the present trial did not contain these components. As part of the manufacturing process, the skin and seeds are removed when making tomato paste and tomato sauce. There may potentially be anticarcinogenic constituents in the skin and/or seeds of whole tomatoes. Another difference between the study by Boileau, et al. and the present study is a lower dose of dietary lycopene was provided to mice in the tomato powder group (13mg lycopene/kg diet) relative to the beadlet groups (161mg lycopene/kg diet) in the study by Boileau et al., whereas in the present study an equivalent dose of lycopene was provided in the TP and LB diets. It may be that the lower dose of lycopene used in the trial by Boileau, et al. had greater chemopreventive effects than the higher dose used in the group that received the lycopene beadlet supplemented diet. Further preclinical studies are required evaluating the dose response effects of lycopene and evaluating the different components of whole tomatoes for prostate cancer chemoprevention.
In the present trial the ratio of 5-cis to trans
- lycopene in the serum was higher in the LB group relative to the TP group. Lycopene has a series of conjugated double bonds and is sensitive to cis-trans
isomerization. Diet-derived lycopene is primarily in the trans
- form, whereas cis
-lycopene appears to be more bioavailable and may be a better substrate to carotene oxygenases than the trans
] The biologic activity of lycopene may be due, in part, to its metabolites.[21
] Lycopene and its metabolites may play a role in chemoprevention through a variety of mechanisms including antioxidant effects, effects on gap junction communications, retinoid signalling, induction of phase-2 detoxification enzymes, and effects on proliferation and apoptosis.[20
] Further studies are required to elucidate if the isomerization state of lycopene plays a significant role in chemoprevention of prostate cancer.
Whereas several trials demonstrated that dietary lycopene decreases serum IGF-I levels and increases serum IGFBP-3 levels, other studies did not confirm these findings.[22
] Herzog, et al., demonstrated decreased local expression of IGF-I in the prostates of rats given lycopene supplementation.[24
] Liu, et al., found that lycopene decreased cell IGF-I production and inhibited IGF-I mediated cell growth.[25
] In the present trial, there was no difference in serum IGF-I and IGFBP-3 levels between the control, TP and LB groups. However, the IGFBP-3 results, while not significant, represent an increase with lycopene supplementation, consistent with previous findings by other groups.[22
] TRAMP mice are known to have progressive increases in serum IGF-I levels and in prostate tissue IGF-I mRNA expression during androgen sensitive prostate cancer development.[26
] However, reduction of liver-derived IGF-I and the resultant reduction in serum IGF-I levels in TRAMP with a targeted deletion of liver-derived IGF-I did not inhibit the development of prostate cancer at 9 and 19 weeks of age.[14
] Interestingly, a recent study in patients at risk for cancer valuated the effects of 8-weeks lycopene intervention and detected increases in IGFBP-1 as the main effect on the IGF system. In this study IGFBP-1 levels were not measured, however, this represents an additional potential mechanism for the actions of lycopene on tumor progression and should be evaluated in future studies.[27
Limitations of this study include a relatively small sample size of 59 mice. The TP group had a 15% lower incidence of prostate cancer relative to the control group but the p-value was 0.34. With a larger sample size we may have potentially seen significant chemopreventive effects with the TP diet. Another potential shortcoming is that serum and prostate tissue levels of lycopene and liver oxidative DNA damage was measured after a 3-week experiment in wild-type mice with the same genetic background as TRAMP mice. We performed this abbreviated experiment because we did not have sufficient serum from the TRAMP mice we studied, and we did not collect liver tissue from the TRAMP mice at sacrifice. In addition, these results may have been different at different time points of progression in TRAMP mice. The lycopene beadlet contained 5% ascorbyl palmitate as an antioxidant, which was not present in the vitamin mix added to the diets. This difference is unlikely to account for the results seen in the present trial given that the ascorbyl palmitate makes up an extremely small fraction of the total diet once the beadlets are mixed with the other components of the experimental diets