Cipolla BG, Havouis R, Moulinoux JP. Polyamine reduced diet (PRD) nutrition therapy in hormone refractory prostate cancer patients. Biomed Pharmacother. 2010;64(5):363-368.
Forty-two patient volunteers with hormone refractory prostate cancer (HRPC) were enrolled in the study. The intervention group (n=26) adhered to a polyamine-reduced diet. They also underwent a partial gut decontamination protocol in which they were given either neomycin or nifuroxazide every other week. The remaining 16 participants did not eat a special diet nor take antimicrobial medication. Parameters measured include World Health Organization (WHO) performance status, European Organisation for Research and Treatment of Cancer (EORTC) pain scale, body weight, blood counts, and serum proteins.
The diet was well-tolerated, and mean observance was 25 (±24) months. Performance status and pain were significantly improved at both 3 months (P = 0.03) and 6 months (P = 0.02) versus baseline. Of note, the intervention in this trial was significantly better if implemented within 9 months of diagnosis to a hormone refractory status. Median cancer-specific survival times for patients beginning the diet before the 9-month cut-off are 44 months, versus 34 months for those beginning later (P =0.014). Median cancer-specific survival times for the intervention groups as a whole compared to controls are 36 months versus 17 months, respectively (P = 0.004).
HRPC is defined by the ineffectiveness of lowering testosterone, via either castration or antiandrogenic drugs, in controlling growth of prostate cancer. The prognosis for these patients is poor as HRPC does not respond well to chemotherapeutic agents. The most recent reports of survival data can be gleaned from clinical trials for the newly approved antineoplastic agent, sipuleucel-T (Provenge®). This immune-modulating therapy was given FDA approval in April 2010, based on increasing the mean overall survival of HRPC patients from approximately 21 months to 25 months.1
Polyamines (ie, putrecine, spermidine, spermine) increase cell proliferation and have been found to exist in higher concentration in cancer cells, including prostate cancer.2 There are 3 sources of polyamines: 1) naturally occurring in foods and beverages, 2) gut microbe production, and 3) intracellular synthesis of polyamines. In the early 1990s, rodent studies showed that a triple regime of a polyamine-deprived diet, gut decontamination with antimicrobials, and ingestion of a drug that blocks the first enzyme in its synthesis (ie, ornithine decarboxylase) resulted in significantly decreased tumor growth.3 The authors of the current abstract published much of the early work in rodent models of cancer, which repeatedly showed effective tumor inhibition through polyamine deprivation by targeting all 3 sources of the compounds.4,5,6,7,8
In this study the dietary intervention consisted of dividing foods and beverages into three groups. Group 1 was foodstuffs with less than 100 nmol/g/ml, which could be eaten freely. Group 2 was foods with 101–200 nmol/g/ml, which could be ingested 3–4 times per week. Group 3 had greater than 201 nmol/g/ml of polyamine concentration and were forbidden except for 2 times every 7 days.
This dietary protocol is strikingly different than what we might consider a good diet. For starters, our assumption is that gut microflora are beneficial; we would rarely encourage purposefully taking antibiotics to wipe them out. Second is the removal of foods we would otherwise consider highly nutritious. For example, Group 3 includes garlic, cabbage, broccoli, tomatoes, almonds, bananas, mushrooms, and sauerkraut. Conversely, Group 1, which was the category that could be freely eaten, includes pork products, canned vegetable soup, dairy products (except aged cheeses), beer, coffee, and pound cake. The authors, who are French, list chocolate éclairs in the group of foods that can be freely consumed. This diet clearly diverges from anything we would have until now routinely advocated for our patients.
There are many more foods on the list, and there is no perceivable means of memorizing the foodstuffs, so a list of foods must be referred to in order to comply with the diet.
While one would assume it may be difficult for patients to adhere to limiting groupings of foods with no apparent relationship, adherence to the diet was extremely high in this study.
While one would assume it may be difficult for patients to adhere to limiting groupings of foods with no apparent relationship, adherence to the diet was extremely high in this study. Of course, allowing unlimited intake of foods that are considered indulgent by most nutritional standards may explain the good compliance by participants.
Targeting the pool of polyamines produced by gut microbes, the intervention in this study included partial “gut decontamination” with neomycin or nifuroxazide, which consisted of a daily oral dose of the antimicrobial, taken every other week. Among the gut microflora that have been found to produce polyamines are Klebsiella pneumonia, Enterobacter spp. and Serratia spp.9 The fact that antimicrobials were integral in the therapy for these patients reminds us that the basics of overall health, in this case a healthy microflora, should not be discarded as too weak or fundamental to have profound effects in cancer care. Given our understanding of growth suppression of probiotics, it is expected that probiotics would reduce polyamine synthesis in the gut by controlling bacterial growth. Indeed, studies of specific probiotics have demonstrated a reduction in polyamines.10
Ultimately, testing of gut microflora in our patients with HRPC may be indicated, as many of the organisms mentioned above would be noted in a thorough microbial stool test. Natural antimicrobial agents may also be used and the patient retested to assess success of treatment. The judicious use of antimicrobial agents is not out of the question in patients with HRPC, given the gravity of the prognosis and relative risk/benefit that may be had from the drugs.
This trial is small, involving only 42 participants. Nonetheless, results did reach statistical significance, which can only be accomplished when the benefits are quite large in small trials. The dietary intervention has no downside risk, as reducing polyamine consumption does not result in any nutrient deficiencies. Therefore, the risk/benefit ratio for the dietary intervention is certainly favorable, particularly given the poor prognosis of patients with HRPC. Of note, this particular trial was done in France, where the ethnic differences in food choices make it difficult to directly extrapolate the various food groupings that were given to these patients. Also, there was also no objective measurement of polyamine status, such urinary or stool levels that may help to estimate the level at which benefit is conferred.
In addition to the early rodent studies corroborating the effectiveness of polyamine reduction, Cipolla and colleagues published a pilot study of 13 volunteers with HRPC in 2003.11 In this earlier study, pain and performance status were improved during dietary intervention but reverted after discontinuing it. Prostate-specific antigen (PSA) was also assessed. One patient had a > 50% reduction, 3 patients had < 50% reduction, and all others had progressively worsening PSA. The dietary intervention was notably shorter, with mean observance of the diet at 8 (±7) months. Cancer specific survival was 14 (±7) months, which is also much shorter than the current study but may be due to the stoppage of the diet by participants. Also, in this earlier trial, patients began the dietary intervention at a later date from their initial HRPC diagnosis (12 [±8] months) versus the current study (10 [±8] months). The current trial suggests that beginning dietary intervention later confers significantly less benefit.
Clinically, the use of a low-polyamine diet can be assumed to “do no harm” and may indeed confer significant benefit for patients with HRPC. Probiotics also have an extremely favorable side-effect profile and should be considered part of any treatment protocol for HRPC patients. Further workup of gut microflora and treatment of dysbiotic bacteria should be considered as well. The use of drugs that block polyamine synthesis is gaining interest, and future studies may guide their usage and dosage for select cancers. While drug development continues to pursue inhibition of polyamine synthesis, it appears we may be able to help our patients today with diet and gut health, particularly our patients with HRPC.
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1. Drug Facts: Sipuleucel-T. National Cancer Institute Web site. http://www.cancer.gov/cancertopics/druginfo/fda-sipuleucel-T. Accessed June 21, 2010.
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3. Seiler N, Sarhan S, Graffel C, Jones R, Knödgen B, Moulinoux JP. Endogenous and exogenous polyamines in support of tumor growth. Cancer Res. 1990;50:5077-5083.
4. Quemener V, Chamaillard L, Brachet P, Havouis R, Moulinoux JP. [The involvement of polyamines in the malignant proliferative process. The anticancer effect of polyamine deprivation]. Ann Gastroenterol Hepatol (Paris). 1995;31(3):181-188.
5. Moulinoux JP, Quemener V, Cipolla B, et al. The growth of MAT-LyLu rat prostatic adenocarcinoma can be prevented in vivo by polyamine deprivation. J Urol. 1991;146(5):1408-1412.
6. Chamaillard L, Quemener V, Havouis R, Moulinoux JP. Polyamine deprivation stimulates natural killer cell activity in cancerous mice. Anticancer Res. 1993;13(4):1027-1033.
7. Brachet P, Quemener V, Havouis R, Tomé D, Moulinoux JP. Alterations in intestinal uptake of putrescine and tissue polyamine concentrations in tumor-bearing rats. Biochim Biophys Acta. 1994;1227(3):161-170.
8. Moulinoux JP, Darcel F, Quemener V, Havouis R, Seiler N. Inhibition of the growth of U-251 human glioblastoma in nude mice by polyamine deprivation. Anticancer Res. 1991;11(1):175-179.
9. Lavizzari T, Breccia M, Bover-Cid S, Vidal-Carou MC, Veciana-Nogués MT. Histamine, cadaverine, and putrescine produced in vitro by enterobacteriaceae and pseudomonadaceae isolated from spinach. J Food Prot. 2010;73(2):385-389.
10. Linsalata M, Russo F, Berloco P, et al. Effects of probiotic bacteria (VSL#3) on the polyamine biosynthesis and cell proliferation of normal colonic mucosa of rats In Vivo. 2005;19(6):989-995.
11. Cipolla B, Guillé F, Moulinoux JP. Polyamine-reduced diet in metastatic hormone-refractory prostate cancer (HRPC) patients. Biochem Soc Trans. 2003;31:384-387.