Journal of the American College of Nutrition, Vol. 20, No. 90005, 443S-449S (2001)
Published by the American College of Nutrition
Can Dietary Methionine Restriction Increase the Effectiveness of Chemotherapy in Treatment of Advanced Cancer?
Daniel E. Epner, MD
Baylor College of Medicine, Houston, Texas
Address correspondence to: Daniel E. Epner, MD, FACP, VA Medical Center, Medical Service (111H), 2002 Holcombe Blvd, Houston, TX 77030. E-mail: depner{at}bcm.tmc.edu
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ABSTRACT
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Most metastatic tumors, such as those originating in the prostate, lung, and gastrointestinal tract, respond poorly to conventional chemotherapy. Novel treatment strategies for advanced cancer are therefore desperately needed. Dietary restriction of the essential amino acid methionine offers promise as such a strategy, either alone or in combination with chemotherapy or other treatments. Numerous in vitro and animal studies demonstrate the effectiveness of dietary methionine restriction in inhibiting growth and eventually causing death of cancer cells. In contrast, normal host tissues are relatively resistant to methionine restriction. These preclinical observations led to a phase I clinical trial of dietary methionine restriction for adults with advanced cancer. Preliminary findings from this trial indicate that dietary methionine restriction is safe and feasible for the treatment of patients with advanced cancer. In addition, the trial has yielded some preliminary evidence of antitumor activity. One patient with hormone-independent prostate cancer experienced a 25% reduction in serum prostate-specific antigen (PSA) after 12 weeks on the diet, and a second patient with renal cell cancer experienced an objective radiographic response. The possibility that methionine restriction may act synergistically with other cancer treatments such as chemotherapy is being explored. Findings to date support further investigation of dietary methionine restriction as a novel treatment strategy for advanced cancer.
Key words: methionine restriction, cancer treatment, chemotherapy, synergism
Key teaching points
• Methionine is an essential amino acid that is particularly abundant in foods rich in animal protein.
• Dietary methionine restriction inhibits growth and causes death of a variety of cancers growing in culture and as tumors in animals. Yet, methionine restriction is relatively well tolerated by normal tissues.
• Preliminary clinical trials in patients with advanced cancer indicate that dietary methionine restriction offers promise as a novel treatment strategy.
• A synergistic effect between methionine restriction and other treatment modalities may improve cancer outcome or at least reduce the adverse side effects of treatments such as chemotherapy.
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INTRODUCTION
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Recent clarification of the molecular pathogenesis of cancer has led to the identification of several novel treatment strategies for advanced cancer. One such strategy is dietary restriction of the essential amino acid methionine. This paper reviews the history of amino acid restriction as cancer treatment, selective antitumor activities of methionine restriction in cell culture and experimental animal studies, specialized functions and metabolism of this amino acid, and potential synergistic effects between methionine restriction and other cancer treatment modalities. We also describe promising preliminary results of a phase I clinical trial of dietary methionine restriction for patients with advanced cancer.
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BACKGROUND
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Smoking cessation, consumption of diets rich in fruits and vegetables, avoidance of excessive sun exposure, and other lifestyle measures can prevent the majority of cancers [1]. Unfortunately, implementation of these conceptually simple measures remains elusive. As a result, each year hundreds of thousands of Americans develop metastatic cancer. Chemotherapy cures only a few types of metastatic cancer, including certain hematological malignancies, germ cell tumors, and a small fraction of other tumors. Unfortunately, the vast majority of common metastatic cancers, including those originating in the breast, prostate, gastrointestinal tract, and lung, are lethal. We therefore desperately need novel treatment strategies for metastatic cancer. Dietary methionine restriction is one such strategy.
Dietary amino acid restriction for the treatment of cancer is not a new concept. Animal experiments published in the early 1900s focused on the potential antitumor activity of dietary protein or amino acid restriction [2]. These initial studies demonstrated no antitumor activity, leading Drummond in 1917 to conclude "it is not possible to bring about an inhibition of tumor growth by an employment of dietary restrictions" [2]. This pessimistic conclusion, however, was not justified in light of later, more sophisticated studies involving chemically defined diets. In 1959, Sugimura and colleagues [3] studied the antitumor activity in tumor-bearing animals of diets lacking one essential amino acid. They found that tumor growth in animals was considerably slowed by diets lacking methionine, isoleucine, or valine. Of the three diets, the methionine free diet was the least toxic, which strongly indicates that dietary methionine restriction has highly specific effects on tumors and host tissues and does not represent indiscriminate tumor "starvation."
Shortly after the study by Sugimura and colleagues [3], several investigations focused on phenylalanine and tyrosine restriction to treat melanoma [4–6]. Phenylalanine and tyrosine are required for the synthesis of melanin, an abundant pigment in melanomas and melanocytes. In 1966, Demopoulos [6] described the results of a phase I clinical trial of dietary phenylalanine and tyrosine restriction for treatment of patients with metastatic melanoma. Remarkably, three of the five patients treated responded to the therapy and experienced minimal toxicity. Results of additional pilot studies were equally promising [4,5]. Unfortunately, examination of the effect of phenylalanine and tyrosine restriction was not pursued aggressively in the clinic thereafter, presumably because it was found to be somewhat "cumbersome, complex, and unpalatable" [6]. Nonetheless, studies of phenylalanine and tyrosine restriction strongly support the concept of amino acid restriction for the treatment of cancer, and excellent mechanistic studies are still underway [7,8].
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TUMOR GROWTH INHIBITORY EFFECTS OF METHIONINE RESTRICTION
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Beginning in the early 1970s, many studies focused on the potential antitumor activity of methionine restriction. Mammalian cells cannot synthesize methionine from any of the other standard amino acids but can remethylate homocysteine to methionine [9]. Normal cells can therefore grow in culture when methionine is replaced by homocysteine in the growth medium [10], and animals fed diets in which methionine has been replaced by homocysteine suffer no ill effects and grow normally [11,12]. In contrast, a wide variety of cancer cell lines are methionine dependent even in the presence of homocysteine.
Numerous cell culture studies using normal and malignant cell lines (e.g., leukemia, prostate) demonstrated that methionine restriction suppresses cancer cell growth, with little or no deleterious effect on normal cells [13–18]. Likewise, tumors are methionine dependent in vivo. Dietary methionine restriction causes regression of a variety of animal tumors and inhibits metastasis in animal models [12,17,19–22]. For example, altering the dietary arginine-methionine balance inhibited tumor growth without causing cachexia in rats with subcutaneously transplanted Morris hepatoma [21,22]. Also, substituting homocysteine for methionine reduced tumor growth and metastasis in a rat rhabdomyosarcoma cell line [12,17]. In addition, many fresh patient tumors in primary histoculture and human tumor xenografts in nude mice are methionine dependent [23,24].
Methioninase, an enzyme that specifically degrades methionine and homocysteine, inhibits growth of a variety of cancer cells in culture as well as solid tumors and leukemia in animals [13,25–33]. Animal studies also support an anti-tumor effect of methioninase [27,28,30]. In laboratory animals with Lewis lung carcinoma, synergistic antitumor activity was demonstrated between methioninase and the chemotherapy drug 5-fluorouracil [30]. In an orthotopic lung cancer model, recombinant methioninase plus methioninase gene therapy was effective in suppressing cancer [34]. The fact that methioninase inhibits tumor growth in preclinical models further supports the concept of dietary methionine restriction as cancer treatment. Recombinant methioninase was recently tested in a phase I clinical trial in Mexico. Patients in the trial experienced no significant toxicity, and plasma methionine levels fell dramatically as expected [35,36]. The antitumor activity of methioninase was not assessed in this trial. A polyethylene glycol conjugation of methioninase has been developed to reduce the potential antigenicity and lengthen the half-life of the recombinant enzyme [37,38].
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MOLECULAR MECHANISMS FOR THE TUMOR INHIBITORY EFFECT OF METHIONINE RESTRICTION
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Determining the molecular mechanisms for the tumor specific growth inhibitory effects of methionine restriction will require an understanding of the specialized functions of methionine. Methionine is the major methyl donor for methylation of DNA, RNA, proteins, and other molecules. Overall rates of methylation are much higher in tumors than in normal tissues [39–41]. Cytosine methylation within CpG islands is one of the mechanisms by which gene expression is regulated [42]. Several growth inhibitory and pro-apoptotic genes are transcriptionally silenced in tumors as a result of focal DNA hypermethylation. DNA methylation also compacts and stabilizes chromatin structure and decreases its susceptibility to DNA-damaging agents. Loss of methylated cytosines reduces the stability of chromatin by decreasing binding sites for methyl-specific DNA-binding proteins [43]. In the absence of methyl-directed protein binding, affected DNA sequences are rendered more accessible to oxidant and/or enzyme-induced DNA strand breakage [44–47]. Animal studies have demonstrated that severe, prolonged methyl deficiency induced by dietary restriction of methionine, choline, homocysteine, and folate leads to global demethylation of normal liver DNA and resultant increased susceptibility to DNA strand breaks [44]. Inhibition of DNA methylation by methionine restriction may therefore make cancer cell DNA susceptible to damage.
Methionine is also required for synthesis of polyamines, which have far-ranging effects on nuclear structure and cell division [48], and for glutathione homeostasis. Glutathione (
-glutamylcysteinylglycine) is a ubiquitous tripeptide that reduces oxidative stress in cells. Oxidative stress is primarily due to reactive oxygen species generated from mitochondrial respiration that are known to damage nuclear and mitochondrial DNA, as well as many other molecules [49,50]. Certain toxins and drugs, such as cancer chemotherapy drugs, also cause oxidative stress. Many tumors contain elevated levels of glutathione that confer resistance to a variety of chemotherapy drugs [51,52]. Methionine maintains intracellular glutathione levels by acting as a sulfur donor for synthesis of cysteine and by preventing efflux of glutathione from within cells [53,54]. Therefore, methionine restriction potentially could inhibit tumor growth by inducing oxidative DNA damage in cancer cells.
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ACHIEVING SYNERGY BETWEEN METHIONINE RESTRICTION AND OTHER TREATMENTS
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Dietary methionine restriction may act synergistically with other cancer treatments to increase their efficacy and/or reduce their toxic side effects. There are several potential strategies for achieving synergy between methionine restriction and other treatments. One such strategy is to combine dietary methionine restriction with methionine analogs. For instance, several studies have demonstrated that methionine restriction and the methionine analog ethionine (S-ethyl-L-homocysteine) have synergistic antitumor activity against a variety of tumors, including prostate cancer and sarcoma [18,55–58]. Other methionine analogs, including selenomethionine, as well as polyamine analogs, SIBA (an analog of S-adenosylhomocysteine), and trifluoromethylhomocysteine have also shown promise in animal studies in combination with methionine restriction [57–63]. Another approach to maximize the antitumor activity of methionine restriction is to target chemotherapy to tumors by restricting dietary methionine and then giving methionine conjugated to an anticancer drug, such as mitomycin C [64].
Dietary methionine restriction has also been combined with methioninase treatment to achieve maximal methionine depletion, as shown in human brain tumor xenografts in athymic mice [31]. Methioninase is being developed by a pharmaceutical company and hopefully will soon be available for clinical trials in the U.S.
Another potential strategy for optimizing the clinical effectiveness of methionine restriction will be to combine it with chemotherapy. Several preclinical studies have demonstrated synergy between methionine restriction and various cytotoxic chemotherapy drugs, such as 5-fluorouracil [30,65,66]. Methionine restriction is thought to enhance the antitumor activity of 5-fluorouracil by raising levels of 5,10-methylenetetrahydrofolate, which is the same mechanism by which leucovorin modulates 5-FU action. In Yoshida sarcoma bearing rats, methionine +/- cysteine restriction enhances the antitumor activity of 5-fluorouracil [65]. Likewise, a synergistic beneficial effect of methionine-depletion and 5-fluorouracil has been demonstrated in gastric cancer xenografts in nude mice [66]. Cisplatin, another commonly used chemotherapy drug, acts synergistically with methionine restriction by inhibiting methionine uptake in tumors, as demonstrated with animal breast cancer and colon cancer models [25,67]. Methionine restriction has also shown promise in animal studies in combination with vincristine [68], the alkylating agents ACNU [69] and CCNU [70], and the anthracycline doxorubicin [71,72]. The optimal sequence and schedule for combining methionine restriction with chemotherapy will need to be determined empirically. One possible approach will be treat patients with "cyclic" methionine restriction, in much the same way as cancer patients are treated with "cycles" of chemotherapy. Patients who are on methionine-restricted diets could be allowed to resume normal diets briefly at regular intervals. In this scenario, chemotherapy would most likely be given during the brief periods of methionine repletion. Preclinical studies involving human carcinoma and sarcoma cell lines lend support to this approach. In those studies, methionine restriction was combined with doxorubicin for 10 days, and cells were then treated with methionine repletion plus vincristine [10]. Clinical trials of various sequences and schedules should become feasible in the near future following completion of the ongoing phase I clinical trial of dietary methionine restriction, described below.
Ultimately, optimization of dietary methionine restriction will depend upon clarification of the molecular mechanisms by which methionine restriction inhibits tumor growth. For instance, the fact that methionine restriction causes certain cancer cells to enter G2 cell cycle arrest [18] may be exploitable therapeutically. Cancer cells that are forced to leave G2 and reenter the cell cycle prematurely following exposure to chemotherapy die much more rapidly than those remaining in G2 [73–75]. "Abrogation" of G2 cell cycle arrest therefore accelerates cancer cell death. Perhaps drugs that abrogate G2 arrest can be used to increase the efficacy of dietary methionine restriction. Additional studies demonstrating that methionine restriction inhibits cyclin dependent kinases [76], modulates glutathione (GSH) levels [53,54,77–81], and possibly inhibits transmethylation of DNA and other molecules [39,40,70,82–86] may also lead to the development of strategies for optimizing the effectiveness and minimizing the toxicity of methionine restriction.
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CLINICAL FEASIBILITY AND POTENTIAL EFFICACY OF DIETARY METHIONINE FOR TREATMENT OF ADVANCED CANCERS
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Based on the strength of many preclinical studies and one small clinical study involving preoperative methionine restriction for patients with localized gastric cancer [87], we initiated a phase I clinical trial of dietary methionine restriction for adults with advanced solid tumors at Baylor College of Medicine and the Houston VA Medical Center. Twelve patients have enrolled so far. Patients in the trial have been prescribed a medical food that provides 0.8 g methionine-free protein/kg/day, 35 kcal/kg/day, vitamins, minerals, and all standard amino acids other than methionine. Participants consume no methionine for the first two weeks. Thereafter, their methionine intake is restricted to 2 mg/kg/day, which is about 5–10% of normal intake. Participants receive no cancer treatments other than the dietary modification.
Dietary methionine restriction has reduced plasma methionine levels from 22 (±6) µM to 9 (±2) µM within eight weeks without affecting levels of other amino acids or albumin. The observed reduction in plasma methionine levels is therapeutically relevant, since similar reductions inhibit growth of human cancer cells in culture. The fact that serum albumin levels have remained stable indicates that the experimental diet does not indiscriminately block protein synthesis. Side effects include weight loss of approximately one pound per week and mild fatigue, both of which are reversible.
Although the trial was designed primarily to assess safety, it has yielded preliminary evidence of antitumor activity. Patients have remained in the trial for 2–39 weeks. One patient with hormone independent prostate cancer experienced a >25% reduction in serum prostate-specific antigen (PSA) after 12 weeks on the trial, and another patient with progressive renal cell carcinoma experienced a radiographic objective response. These results, although very preliminary, strongly suggest that dietary methionine restriction has antitumor activity.
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CONCLUSION
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Despite many promising preclinical and clinical studies in recent years, dietary methionine restriction and other dietary approaches to cancer treatment have not yet gained wide clinical application. Most clinicians and investigators are probably unfamiliar with nutritional approaches to cancer. Many others may consider amino acid restriction as an "old idea," since it has been examined for several decades. However, many good ideas remain latent for decades if not centuries before they prove valuable in the clinic. For example, who would have anticipated that arsenic, which has been used as both a medicine and toxin for centuries, would prove to be a highly effective, modern treatment for acute leukemia [88]? With the proper development, dietary methionine restriction, either alone or in combination with other treatments, may also prove to have a major impact on patients with cancer.
Received April 26, 2001.
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