Methionine Dependency.

[pjoshea13]

New(?) study below [1].

Not a new topic. A 1993 study [2] looked at a variety of human cancer tissues:

"We found that 5 human tumors of 21, including tumors of the colon, breast, ovary, prostate, and a melanoma, were methionine dependent based on cell cycle analysis."

The new study looks suspiciously similar. & Robert M. Hoffman is the author of both (25 years apart).

Some will remember methionine from threads on the SAM cycle:

... Methionine--->SAM(SAMe)--->Homocysteine+Methyl--->Methionine ...

SAM is the universal donor of methyl throughout the body. Although SAM is derived from methionine, it appears that dietary methionine does not meet the need. When SAM drops off its methyl we are left with circulating homocysteine. This can be recycled back to methionine if there are other dietary methyl donors, of which, folate is the most important. When dietary methyl is insufficient, homocysteine becomes elevated. (High homocysteine is associated with health issues, but intervention studies with folic acid (supplying the folate) & cofactors - particularly vitamin B12 - have not reduced risk, even though homocysteine levels were reduced.)

PCa cells are generally hypermethylated. Methyl is used to silence the promoter regions for tumor suppressor genes.

But the cells will also take up methionine.

In normal cells that are starved of methionine [MET], but not homocysteine [HCY], cell division is not affected. But in a significant fraction of cancer cases, cells are dependent on methionine & cannot manufacture it via homocysteine. Methionine starvation might halt tumor cell division in some patients (across all solid tumor types).

[3] (1997): "Alterations of MET metabolism have been observed in in vitro culture tumour cells (Mechametal,1983), and their MET dependency was described as the inability of MET-dependent cells to grow in MET medium, the need for a higher MET supply than that of normal cells and as the inability to use HCY as a precursor for endogenous MET synthesis. Therefore, MET dependency led to the formulation of MET-free diets to feed rats or mice bearing experimental tumours (Breillout et al, 1987, 1990; Fiskerstrand et al, 1994). In these diets, an amino acid mixture replaced proteins and HCY replaced MET. HCY substitution was required for animal survival and was well tolerated (Gaudard-de Weck, 1989)."

More recently (2012), an Australian paper [4] tried to revive interest:

"Methionine is an essential amino acid with many key roles in mammalian metabolism such as protein synthesis, methylation of DNA and polyamine synthesis. Restriction of methionine may be an important strategy in cancer growth control particularly in cancers that exhibit dependence on methionine for survival and proliferation. Methionine dependence in cancer may be due to one or a combination of deletions, polymorphisms or alterations in expression of genes in the methionine de novo and salvage pathways. Cancer cells with these defects are unable to regenerate methionine via these pathways. Defects in the metabolism of folate may also contribute to the methionine dependence phenotype in cancer. Selective killing of methionine dependent cancer cells in co-culture with normal cells has been demonstrated using culture media deficient in methionine. Several animal studies utilizing a methionine restricted diet have reported inhibition of cancer growth and extension of a healthy life-span. In humans, vegan diets, which can be low in methionine, may prove to be a useful nutritional strategy in cancer growth control. The development of methioninase which depletes circulating levels of methionine may be another useful strategy in limiting cancer growth. The application of nutritional methionine restriction and methioninase in combination with chemotherapeutic regimens is the current focus of clinical studies."

A French paper from 2003 [5] made some important points:

"... prolonged methionine restriction with diet or with methioninase is not suitable for clinical use."

"Methionine restriction may find greater application in association with various chemotherapeutic agents. Several preclinical studies have demonstrated synergy between methionine restriction and various cytotoxic chemotherapy drugs. The experimental results accumulated during the last three decades suggest that methionine restriction can become an additional cancer therapeutic strategy, notably in association with chemotherapy."

...

Robert Hoffman [6]:

"Dr. Robert M. Hoffman of AntiCancer, Inc., has discovered a breakthrough: When cancer cells are deprived of methionine, the cancer cell dies. Applicable to all types of cancer, Dr. Hoffman has utilized the HHS SBIR program to further this research, and he feels the promise of a cancer-free future is well within our reach. The treatment, called L-Methionine-g-lyase, comes in the form of an injectable protein, which does not need to reach the tumor. Rather, it only needs to reach the bloodstream, and it gets to work immediately by breaking down methionine in the body, which does not disrupt the function of normal, healthy cells. A partnership with a major biotechnology company will further fuel this research."

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/295...

Methods Mol Biol. 2018;1760:125-131. doi: 10.1007/978-1-4939-7745-1_13.

Methionine Dependency Determination of Human Patient Tumors in Gelfoam® Histoculture.

Hoffman RM1,2.

Author information

1

AntiCancer Inc., San Diego, CA, USA. [e-mail].

2

Department of Surgery, University of California, San Diego, CA, USA. [e-mail].

Abstract

The elevated requirement of methionine by cancer cells (methionine dependence) is a general metabolic abnormality in cancer. Methionine-dependent cancer cells are unable to proliferate and arrest in the late S/G2 phase of the cell cycle when methionine is restricted in vitro or in vivo. Cell-cycle arrest in late S/G2 was used as a biomarker of methionine dependence for patient tumors in Gelfoam® histoculture. Human cancer patient tumors, including tumors of the colon, breast, ovary, prostate, and a melanoma, were observed to be methionine dependent in Gelfoam® histoculture based on cell cycle analysis. This simple method can be used to screen patient tumors for methionine dependence and then subsequently apply appropriate chemotherapy for these patients to target this cancer-specific metabolic abnormality.

KEYWORDS:

Cell-cycle block; Gelfoam® histoculture; Human tumors; Methionine dependence; Methionine restriction; S/G2 phase

PMID: 29572800 DOI: 10.1007/978-1-4939-7745-1_13

...

[2] cancerres.aacrjournals.org/...

[3] ncbi.nlm.nih.gov/pmc/articl...

[4] ncbi.nlm.nih.gov/pubmed/223...

[5] ncbi.nlm.nih.gov/pubmed/145...

[6] sbir.gov/sites/default/file...

[JLS1]

I couldn't 'digest' the whole article, but I love this part at the end!:

-and it shouldn't take too long to find out if it does indeed work, esp if it's as safe, as it sounds

"Dr. Robert M. Hoffman of AntiCancer, Inc., has discovered a breakthrough: When cancer cells are deprived of methionine, the cancer cell dies. Applicable to all types of cancer, Dr. Hoffman has utilized the HHS SBIR program to further this research, and he feels the promise of a cancer-free future is well within our reach. The treatment, called L-Methionine-g-lyase, comes in the form of an injectable protein, which does not need to reach the tumor. Rather, it only needs to reach the bloodstream, and it gets to work immediately by breaking down methionine in the body, which does not disrupt the function of normal, healthy cells. A partnership with a major biotechnology company will further fuel this research."

[Canoehead]

Methionine is an essential amino acid involved in the creation of cartilage and may also help prevent hair loss and strengthen nails. A deficiency of methionine can lead to inflammation of the liver (steatohepatitis), anemia, and greying hair. However, a diet low in methionine may also extend lifespan and reduce risk of cancer. High methionine foods include nuts, beef, lamb, cheese, turkey, pork, fish, shellfish, soy, eggs, dairy, and beans. For people looking to build muscle, the bioavailability of methionine is greater in animal foods, particularly dairy. Soy and beans, while a source of methionine, may be suboptimal, though more research needs to be done. The recommended daily intake for methionine is 10.4mg per kilogram of body weight, or 4.5mg per pound. A person weighting 70kg (~154 pounds) should consume around 728mg of methionine per day.

[Captain_Dave]

During a visit to my onco, I had a file folder full of articles. I was paging thru them and he saw one of my articles about Methionine Restriction and Cancer. He stopped me and pointed to that article and said "that is very true!"

-Dave

[Captain_Dave]

Here is a link to an article on methionine content of foods.

benbest.com/calories/Meth.html

[BigRich in reply to Captain_Dave]

Interesting read; however, very difficult to incorporate into your diet. I have small portions of fish and chicken. I like to have 6 oz. 4 times a week; 3oz of red meat once week. A lot of fruit and veggies are eaten.

I used to eat over 370 oz, a month of red meat. Now, I eat 12 oz. a month, I didn't eat red meat for 5 years. Then I decided 12 oz. a month was not going to kill me.

Rich

[Hidden]

After reading your post and examining the lists on the link to methionine content of foods I can see where dairy and red meat are on the list of foods to avoid. There were other thing to avoid, like certain nuts, that were surprising. Changing my diet is going to be easier said than done but it starts with awareness. Thanks for the post.

[jdm3]

This is an interesting site I stumbled across while researching other stuff. May be of some interest. There are several references to limiting methionine... and glutamine (also discussed in this forum)

integrativeoncology-essenti...

Edited to add that there was a discussion about eggs and egg whites somewhere else (can't find it) and apparently egg whites are high in methionine. Arrrgh. Too bad. I though I could avoid the choline in the yolks and still have my eggs, but no such luck.