Polyamine reduced diet (PRD) nutrition therapy in hormone refractory prostate cancer patients

doi:10.1016/j.biopha.2009.09.022

Biomedicine & Pharmacotherapy

Volume 64, Issue 5, May 2010, Pages 363-368

https://doi.org/10.1016/j.biopha.2009.09.022 Get rights and content

Abstract

Background

Reducing polyamine uptake by selecting low polyamine-containing foodstuffs and reducing bacterial gut production can improve performance status and pain control in hormone refractory prostate cancer (HRPC) patients. Long term PRD observance and tolerance were assessed. Cancer specific survival was studied in function of PRD and time of PRD initiation.

Methods

Twenty-six volunteers, age: 68 ± 10 years with metastatic HRPC accepted a polyamine reduced diet and partial gut decontamination with oral neomycin or nifuroxazide (750 mg daily, one week out of two). Time from HRPC to PRD initiation was 10 ± 8 months. WHO performance status, EORTC pain scale, body weight, blood counts and serum proteins were regularly assessed. Sixteen other HRPC patients eating a normal diet served as “controls”.

Results

Mean diet observance is 25 ± 24 months. Tolerance is good. WHO performance status and EORTC pain scales were significantly improved respectively at 3 months (0.5 ± 0.7 vs 0.7 ± 0.9: p = 0.03) and 6 months (0.5 ± 0.8 vs 1 ± 1.3, p = 0.02) compared to initial values. Median cancer specific survival times after HRPC and PRD initiation are respectively 36 and 21 months. Eleven PRD patients started the diet before a 9 months cut-off period (after HRPC) and 15 patients after. Median cancer specific survival times for these two groups of patients are respectively 44 and 34 months, p = 0.014. Median cancer specific survival times (after HRPC) for PRD patients compared to controls are 36 vs 17 months (p = 0.004).

Conclusions

Polyamine-reduced diet is well observed and tolerated. It seems to improve and/or maintain quality of life for HRPC patients. Early PRD initiation in HRPC is promising and may impact favorably cancer specific survival. These results open a rationale for PRD in HRPC management and warrant further investigation.

Introduction

The incidence of prostate cancer is increasing and is now the most common male cancer in the Western world. Cure is possible if the disease is radically treated in its early stages, but no curative therapy exists in advanced stages when hormonal escape inevitably occurs and the best palliation possible is the most we can offer.

The polyamines (PA) belong to a very wide range of biogenic amines that are involved in many physiological functions [1]. These ubiquitous chemical entities are believed to participate in cellular proliferation and differentiation. In mammals, cellular PAs (i.e., putrescine, spermidine [Sd], spermine [Sm]) derive from endogenous biosynthesis, as well as from the diet and from intestinal microorganisms. Putrescine (Pt) is synthesised from ornithine by a reaction catalysed by ornithine-decarboxylase (ODC), the limiting enzyme in PA synthesis. The other two mammalian PAs derive from putrescine by successive attachment of two propylamine groups by the action of aminopropyl-transferases, namely Sd and Sm synthase. The propylamine group donor is S-adenosyl-S-methyl-homocysteamine derived from S-adenosyl-methionine by the action of SAM-decarboxylase. Abnormalities in the homeostatic control of PAs metabolism are implicated in several pathological processes, including cancer.

The metabolic requirement for PAs is particularly high in rapidly growing tissues, during normal growth and development, and in tumors [2].

In vitro, difluoro-methylornithine (DFMO), an inhibitor of ODC, is an effective inhibitor of malignant cell proliferation, but in vivo the effectiveness of DFMO is reduced by tumour cell uptake of PAs released into the circulation by normal and cancer cells and from gut flora or dietary sources. Tumour-bearing animals fed with a PA deficient diet (PDD) and treated by DFMO and neomycin (partial decontamination of the gastro-intestinal tract), exhibit a very significant inhibition of tumour progression and of metastasis spreading [2], [3], as well as an anticancer immunity stimulation [4], without inducing deleterious secondary effects. Furthermore, we have demonstrated that PA deprivation and low dose cyclophosphamide chemotherapy have synergistic effects [5].

In tumour-grafted animals only fed with PDD and receiving neomycin in the drinking water (i.e., without DFMO), we have observed a 40% inhibition in tumour progression [2]. Given alone, neither neomycin nor DFMO was able to positively modify the malignant evolution.

As previously shown by Bardocz et al. [6], some food ingredients contain large quantities of PAs. As 80% of exogenous PAs are of dietary origin [2], [6], this led us to analyse the PA content of common foodstuffs in an attempt to reduce the PA intake in cancer patients.

A preliminary clinical trial performed in 13 metastatic hormone-refractory prostate cancer (HRPC) patients revealed the feasibility of this nutrition therapy based upon a 6 months PA reduced diet combined with oral neomycin treatment [7]. Reducing PA dietary intake and partial intestinal decontamination is well observed and tolerated. It also seemed to be beneficial for the patient's quality of life: performance status and pain scores were improved during the regimen and deteriorated 3 months after stopping it. No significant modification of other studied biological parameters was noted.

We have recently published the PA contents of 233 foodstuffs and drinks, which can serve as a basis for PRD. Furthermore, PRD tolerance and observance is very good in prostate cancer patients [8].

In this prospective observational study, 26 HRPC patients accepted and continued PRD for as long as they wanted. We present the results relating to its observance, safety and effect on quality of life (performance status and pain control). Cancer specific survival has been assessed for the study population but also in function of early, compared to later PRD initiation. In a non randomized manner, PRD patient survival was compared to “control” patients (HRPC patients eating a normal diet).

Section snippets

Foodstuff and erythrocyte polyamine extraction and determination

Foodstuff and erythrocyte PA extraction and determination were performed as previously described [8], [9], [10].

Food lists

A list of these different foods, drinks and their PA contents was given to each patient who could thus prepare his meals freely. Patients were instructed to follow the diet 5 days a week but could eat what they wanted any other two days. Three groups of foods were established according to their PA contents. Group I (containing < 100 nmol/g/ml PA) could be eaten at will (Table 1), Group

Observance

Mean PRD observance was 25 ± 24, median: 16 (range; 4–100) months. No patient stopped the diet due to intolerance.

Toxicity

No adverse effects due to the diet were observed.

Because of intestinal intolerance (grade 1 diarrhoea or flatulence), eight patients (30%) wished to stop neomycin or nifuroxazide, a median 5 months after initiation. They continued with PRD alone.

Body weight, performance status, pain status, serum haemoglobin, white blood cell count, serum protein, alkaline phosphatases, Prostatic

Discussion

In its early stages, prostate cancer progresses slowly and may be indolent for many years but when it evolves unfavorably and inevitably escapes androgen deprivation, outcome for patients becomes grim with mean survival times varying from 12 to 18 months [11]. At this stage, only palliative treatment can be proposed, focused on quality of life and pain control. Indeed, docetaxel chemotherapy regimens, although statistically improving survival time for a few months, have not yet radically

Conclusions

A PA-reduced diet with intermittent partial intestinal tract decontamination is safe and well observed as nutritional therapy for selected HRPC patients. Long-term observance is possible. Pain is well controlled and performance status maintained, contributing to better quality of life with no specific side effects. Reducing PA uptake could also be beneficial for patient survival, especially if initiated in the early phases of hormonal escape. These results are certainly worthy of further

Conflicts of interest

The authors have not declared any conflict of interest.

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Original articlePolyamine reduced diet (PRD) nutrition therapy in hormone refractory prostate cancer patients

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Foodstuff and erythrocyte polyamine extraction and determination

Food lists

Observance

Toxicity

Discussion

Conclusions

Conflicts of interest

J Urol

Anal Biochem

Life Sci

Life Sci

Eur J Pharmacol

Pain

Pain

A guide to the polyamines

Endogenous and exogenous polyamines in support of tumor growth

Cancer Res

The growth of MAT LyLu rat prostatic adenocarcinoma can be prevented in vivo by polyamine deprivation

J Urol

Polyamine deprivation prevents the development of tumour-induced immune-suppression

Brit J Cancer

In vivo, synergestic inhibition of Mat LyLu rat prostatic adenocarcinoma growth by polyamine deprivation and low dose cyclophosphamide

Urol Res

The importance of dietary polyamines in cell regeneration and growth

Br J Nutr

Original article
Polyamine reduced diet (PRD) nutrition therapy in hormone refractory prostate cancer patients