CORRESPONDENCE

Re: Prostate Carcinogenesis in N-methyl-N-nitrosourea (NMU)–Testosterone-Treated Rats Fed Tomato Powder, Lycopene, or Energy-Restricted Diets

Jacqueline Limpens, Wytske M. van Weerden, Klaus Krämer, Dirk Pallapies, Ute C. Obermüller-Jevic, Fritz H. Schröder

Affiliations of authors: Department of Urology, Erasmus MC, Rotterdam, The Netherlands (JL, WMVW, FHS); BASF Aktiengesellschaft, Ludwigshafen, Germany (KK, UCOJ, DP).

Correspondence to: Fritz H. Schröder, MD, PhD, Department of Urology, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands (e-mail: e.vandenberg{at}erasmusmc.nl)

Epidemiologic studies have suggested that intake of tomatoes and tomato products may lower prostate cancer risk (1). The general belief that lycopene, the predominant tomato carotenoid, may be the major protective substance has recently been challenged by Boileau et al. (2). Using a rat carcinogenesis model, the authors showed that whole tomato powder, as well as dietary restriction, reduced the risk of prostate cancer, whereas a pure synthetic lycopene supplement did not. This finding was discussed in an editorial (3) and was widely covered in the media, where it was translated into the message that a pill can never replace "whole" products or a healthy diet.

Although it is certainly conceivable that the antitumor effects of tomatoes are not attributable to a single agent, the Boileau paper does not prove inefficacy of pure lycopene: only a single dose was tested, and the dose was 10-fold higher than the amount of lycopene in the tomato powder. As addressed in the editorial (3), the lycopene supplement may have been given in a supra-optimal dose.

Recently, we have completed a study (4) that may shed new light on these findings. The effect of two dosages of synthetic lycopene (5 and 50 mg/kg body weight) and vitamin E (alpha-tocopherol acetate; 5 and 50 mg/kg) both alone and, for the lowest dosages, in combination, was evaluated in an orthotopic model of the human prostate cancer cell line PC-346C in nude mice. Supplements were administered orally, once daily. Tumor growth was monitored by transrectal ultrasonography and was related to serum prostate-specific antigen levels (5).

Contrary to what Boileau et al. found, we found that synthetic lycopene inhibited prostate tumor growth and decreased PSA levels in the mouse xenograft model, with this effect reaching statistical significance only in the low-dose lycopene group. This suggests that lycopene dosages might be relevant to their effects. Recently, pure lycopene has also been shown to reduce cancer risk in a ferret lung carcinogenesis model (6).

Vitamin E at the highest dose level slightly, but nonsignificantly, retarded prostate cancer growth. By far the greatest inhibition was observed in mice treated with the low lycopene–low vitamin E mix. This result is consistent with the synergistic inhibition of the growth of prostate carcinoma cells in vitro by lycopene and vitamin E that was reported by Pastori et al. (7).

In conclusion, our experiments show that lycopene has antitumorigenic effects in a prostate cancer model that can be potentiated by vitamin E, an antioxidant that is also present in tomatoes. Because tomatoes might possess both tumor-enhancing and tumor-inhibiting substances, pursuing the identification of ideal combinations of active phytochemicals seems important. Although pills can never replace a healthy diet and lifestyle, a well-defined, safe combination of phytochemicals may turn out to be beneficial as an adjunct to other forms of cancer prevention and treatment.

REFERENCES

1 Giovannucci E. A review of epidemiologic studies of tomatoes, lycopene, and prostate cancer. Exp Biol Med (Maywood) 2002;227:852–9.[Abstract/Free Full Text]

2 Boileau TW, Liao Z, Kim S, Lemeshow S, Erdman JW Jr, Clinton SK. Prostate carcinogenesis in N-methyl-N-nitrosourea (NMU)-testosterone-treated rats fed tomato powder, lycopene, or energy-restricted diets. J Natl Cancer Inst 2003;95:1578–86.[Abstract/Free Full Text]

3 Gann PH, Khachik F. Tomatoes or lycopene versus prostate cancer: is evolution anti-reductionist? J Natl Cancer Inst 2003;95:1563–5.[Free Full Text]

4 van Weerden WM, de Ridder CM, Bolder CA, Wildhagen M, Kraemer K, Schroeder FH. Oral supplementation of vitamin E and lycopene reduces orthotopic growth of PC-346C prostate tumors [abstract 843]. J Urol 2003;169:218.

5 Kraaij R, van Weerden WM, de Ridder CM, Gussenhoven EJ, Honkoop J, Nasu Y, et al. Validation of transrectal ultrasonographic volumetry for orthotopic prostate tumours in mice. Lab Anim 2002;36:165–72.[CrossRef][ISI][Medline]

6 Liu C, Lian F, Smith DE, Russell RM, Wang XD. Lycopene supplementation inhibits lung squamous metaplasia and induces apoptosis via up-regulating insulin-like growth factor-binding protein 3 in cigarette smoke-exposed ferrets. Cancer Res 2003;63:3138–44.[Abstract/Free Full Text]

7 Pastori M, Pfander H, Boscoboinik D, Azzi A. Lycopene in association with alpha-tocopherol inhibits at physiological concentrations proliferation of prostate carcinoma cells. Biochem Biophys Res Commun 1998;250:582–5.[CrossRef][ISI][Medline]



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