Thema: Presse; Study to Probe Effects of Amino Acid on Brain Cancer

New Study to Probe Effects of Amino Acid on Brain Cancer

Cancer Treatment Research Foundation announced today that it is funding a two-year study investigating whether the elimination of the amino acid methionine from the diet, coupled with chemotherapy, provides increased survival and quality of life enhancement for patients suffering from glioblastoma multiforme (GBM), a common and deadly type of brain cancer.

Morris D. Groves, MD, Assistant Professor of Neuro Oncology at MD Anderson Cancer Center at the University of Texas, will conduct the study, which will treat patients with standard chemotherapy combined with a special methionine-free diet. The diet alone should cause some tumor cells to die, but combined with chemotherapy, Dr. Groves anticipates a powerful anti-tumor effect.

"The diet works in many complex ways, but broadly, it turns 'on' genes that help us fight or resist cancer and turns 'off' genes that help cancer cells resist standard therapy," noted Dr. Groves.

In order to remove methionine from the diet, patients will need to replace the protein in their diet with the supplement shake Hominex-2®. As long as the therapy is working and the side effects are limited, the therapy will be continued for up to one year in each patient. In addition to preventing tumor growth, this therapy is expected to improve patients' quality of life by giving them a feeling of control that comes from taking proactive steps to combat their disease.

GBM is a serious and deadly form of brain cancer with an average length of survival after diagnosis of one year. As a result, any extension of life for GBM patients is significant.

"Methionine restriction has the potential to be a breakthrough therapy. If proven beneficial, this treatment can easily be expanded to other cancer types and combined with other chemotherapies. This is exactly the type of innovative, high-impact research Cancer Treatment Research Foundation is privileged to fund," said Kristine Nelson, MD, Vice President of Research for CTRF.

As with all studies funded by CTRF, Dr. Groves' proposal went through a rigorous evaluation by the Foundation's Board of Scientific Counselors. This group of world-renowned scientists ensures that all prospective projects meet the highest standards of scientific merit and proper methodology, and that the studies are in line with CTRF's mission of funding research that will make an immediate difference in the lives of cancer patients - CTRF does not fund any research on animals or basic science at the test-tube level.

CHICAGO, February 23, 2004 - CTRF

Bedeutet das, daß in diesem " Hominex" Aminosäuren enthalten sind, die das normale Eiweiß aus der Nahrung ersetzen sollen? Welche? geht das irgendwo aus dem Artikel hervor?

Man müsste schon etwas mehr wissen. Zum Beispiel, was gegessen werden darf/soll. Metionin ist z. B. in folgenden Lebensmitteln enthalten:

Fisch (Lachs,Garnelen), Fleisch und Gemüsen ( Brokkoli, grüne Erbsen, Rosenkohl, Spinat), Ei, Vollkornbrot und Reis.

Wenn man dann noch alle Lebensmittel mit einem hohen glykämischen Index weglässt, wird es ziemlich eng.

Hallo Karin,
was könnte HOMINEX sein? Vielleicht helfen die Abstracts weiter:


Biochem Pharmacol. 2003 Sep 1;66(5):791-800.
Methionine restriction selectively targets thymidylate synthase in prostate cancer cells.Lu S, Chen GL, Ren C, Kwabi-Addo B
Department of Medicine, VA Medical Center, Baylor College of Medicine, Medical Service (111H), 2002 Holcombe Blvd., Houston, TX 77030, USA.
Tumor cells are more sensitive to methionine restriction than normal tissues, a phenomenon known as methionine auxotrophy. Previous studies showed that 5-fluorouracil and methionine restriction act synergistically against a variety of tumors. The purpose of the current studies was to determine the molecular mechanism(s) underlying this synergy. 5-Fluorouracil is known to inhibit thymidylate synthase (TS), a key enzyme that transfers a methyl group from 5,10-methylene-tetrahydrofolate to dUMP during nucleotide biosynthesis. We found that methionine restriction reduced 5,10-methylene-tetrahydrofolate levels by 75% and selectively inhibited TS activity in PC-3 human prostate cancer cells within 24hr, whereas it did not in normal prostate epithelial cells. The observed fall in TS activity was accompanied by a commensurate reduction in TS protein levels as determined by western blot analysis. In contrast, 5-fluorouracil inhibited TS activity by >90% but increased TS protein levels. This increase was abrogated by methionine restriction. Surprisingly, methionine restriction increased 3H-leucine incorporation in PC-3 cells over the first 24hr, suggesting that reduction of TS levels was not simply due to global protein synthesis inhibition. Methionine restriction also significantly reduced the ratio of dUMP to dTTP in PC-3 cells, creating an imbalanced nucleotide pool. These results suggest that synergy between methionine restriction and 5-fluorouracil is attributable to multiple factors, including depletion of reduced folates, selective inhibition of TS, and creation of an imbalanced nucleotide pool. Dietary and/or enzymatic methionine restriction combined with 5-fluoruracil has great promise as a novel treatment for advanced cancer.

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Annual rept. 23 Apr 2002-22 Apr 2003
Dietary Methionine Restriction: Novel Treatment for Hormone Independent Prostate Cancer
Epner, Daniel E.; BAYLOR COLL OF MEDICINE HOUSTON TX
Many studies have shown that methionine restriction inhibits growth of a variety of human tumor xenografts, including prostate cancers. In contrast, methionine restriction is relatively well tolerated by normal host tissues. The overall goal of the current project is to clarify the molecular mechanisms by which methionine restriction inhibits tumor growth. During the second year of support, we focused on Specific Aim 3, which is to determine whether methionine restriction leads to DNA demethylation in cancer cells. We used Southern blot analysis with methylation-sensitive restriction enzymes, western blot analysis, and RT-PCR to determine whether methionine restriction restored expression of growth inhibitory genes known to be transcriptionally silenced in cancer cells. We studied human prostate, colon, bladder, and leukemia cell lines. Treatment with the demethylating drug 5-azactydine was used as a positive control for DNA demethylation. We found that methionine restriction did not lead to DNA demethylation or re-expression of the genes studied. These results are consistent with published studies showing that DNA demethylation requires cell division, which rapidly ceases in response to methionine - restriction. Future studies will focus on the possible role of methionine restriction in regulation of other critical methyl acceptors, such as RNA and protein.

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Int J Oncol. 2003 Feb;22(2):415-20.
Induction of caspase-dependent and -independent apoptosis in response to methionine restriction. Lu S, Hoestje SM, Choo E
Department of Medicine, Baylor College of Medicine and VA Medical Center, Houston, TX 77030, USA.
Tumor cells are more sensitive to methionine restriction than normal tissues, a phenomenon known as methionine auxotrophy. Previous studies have demonstrated that methionine restriction causes tumor cell growth arrest and eventually apoptosis. The current studies were undertaken to elucidate the molecular pathways leading to apoptosis induced by methionine restriction. We found that methionine restriction induced formation of oligonucleosomal DNA fragment and cytochrome c release from mitochondria in methionine-dependent PC3 and Hela cells. Methionine restriction also led to cleavage and activation of initiator and effector caspases in Hela cells but not PC3 cells. Furthermore, methionine restriction resulted in cleavage of BID and reduction in Bcl-2 levels in both cell lines. These data suggest that apoptosis induced by methionine restriction is mitochondria-dependent. Methionine restriction induced caspase-independent cell death in PC3 cells, whereas it stimulated caspase-dependent cell death in Hela cells. Cleavage of BID and decreased expression of Bcl-2 upon methionine deprivation may be the underlying mechanism to stimulate release of cytochrome c from mitochondria.
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Molecular Endocrinology 14 (5): 753-760
Androgen Induction of Cyclin-Dependent Kinase Inhibitor p21 Gene: Role of Androgen Receptor and Transcription Factor Sp1 Complex . Shan Lu, Guido Jenster
Department of Medicine (S.L., D.E.E.) Baylor College of Medicine Houston, Texas 77030, Department of Urology (G.J.) Erasmus University Rotterdam, The Netherlands
Previous studies have shown that androgen up-regulates expression of the p21 (WAF1, CIP1, SDI1, CAP20) gene, which contains a canonical androgen response element (ARE) in its proximal promoter region. We undertook the current studies to determine whether elements in the p21 promoter other than the ARE mediate androgen action. We found that deletion of the ARE did not completely abolish the promoter responsiveness to androgen, suggesting that additional cis-regulatory elements within the p21 core promoter may also be involved in androgen responsiveness. The p21 core promoter is GC-rich and contains six binding sites for transcription factor Sp1. We determined whether one or more of these Sp1 sites mediate androgen responsiveness of the p21 promoter. To do so, we used a transient transfection assay with p21 promoter-luciferase reporter constructs. The reporter activity of a construct lacking the ARE but containing all six Sp1 sites was induced approximately 3-fold by androgen. Mutation of Sp1-3 nearly eliminated basal promoter activity as well as androgen responsiveness, whereas deletion of Sp1-1 and Sp1-2 sites and mutation of Sp1-4, Sp1-5, and Sp1-6 sites had relatively little effect. We also used the mammalian one-hybrid assay and coimmunoprecipitation assay to show that androgen receptor (AR) and transcription factor Sp1 interact with one another. The current studies suggest a model in which AR and transcription factor Sp1 not only bind to their respective consensus sites within the p21 promoter, but also complex with one another, thereby recruiting coactivators and general transcription factors and inducing p21 transcription.
Copyright © 2000 by The Endocrine Society

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Nutr Cancer. 2000;38(1):123-30.
Molecular mechanisms of cell cycle block by methionine restriction in human prostate cancer cells. Lu S, Epner DE.
Department of Medicine, Baylor College of Medicine and Veterans Affairs Medical Center, Houston, TX 77030, USA.
Previous studies have shown that dietary or pharmacological methionine restriction inhibits growth of human prostate cancer cells in vitro or as xenografts in mice. We undertook the present studies to clarify the molecular mechanisms by which methionine restriction inhibits prostate cancer cell growth. We found that PC-3 and DU 145 cells stopped proliferating within six days in growth medium containing homocysteine in place of methionine. In contrast, proliferation of LNCaP cells was only partially inhibited by the absence of methionine. Using flow cytometry, we found that methionine restriction caused PC-3 cells to arrest in all phases of the cell cycle, but predominantly in the G2/M phase, whereas LNCaP cells accumulated exclusively in the G1 phase. Methionine restriction led to accumulation of the cyclin-dependent kinase inhibitors p21 and p27, as determined by Western blot analysis, and inhibited the enzymatic activities of the cyclin-dependent kinases CDK2 and cdc2, as determined by an in vitro kinase assay: However, methionine restriction had little or no effect on CDK2 or cdc2 protein levels. Methionine restriction also induced PC-3 cells to undergo apoptosis, as indicated by the appearance of a typical nucleosomal ladder on gel electrophoresis of genomic DNA. We conclude that methionine restriction has potential as a novel treatment strategy for prostate cancer.
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5R29CA078355-05
BAYLOR COLLEGE OF MEDICINE GAPDH--NOVEL REGULATOR OF CELL STRUCTURE AND MIGRATION
The long-term objective of this project is to establish the role of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in cell migration, a prerequisite for cancer invasion and metastasis. GAPDH is a multifunctional actin binding protein overexpressed in many human tumors. The GPDH actin-binding region has been identified in preliminary studies by the principal investigator. Specific Aim 1 is to identify individual amino acids within this region that are important for actin binding. This will be accomplished in two ways. First, site-directed mutagenesis will be used to determine which residues are critical for F actin crosslinking by GAPDH in vitro. Second, fusion proteins consisting of wild type and mutant forms of the GAPDH actin binding domain linked to green fluorescent protein will be expressed in prostate cancer cells to determine which residues are critical fo actin binding. Specific Aim 2 is to determine whether inhibition of GAPDH-acti interaction inhibits cell migration. In one series of experiments, prostate cancer cells will be microinjected with a peptide known to inhibit F actin gelation by GAPDH and then analyzed with time-lapse videomicroscopy and computer image analysis. In a second set of experiments, Dictyostelium discoideum will be transformed with the GAPDH sequence mutated at specific residues in the actin binding domain and will then be analyzed with videomicroscopy and other established migration assays. Dictyostelium is a slime mold that has been used extensively as a model system for studying cell migration. Since Dictyostelium is haploid, its endogenous GAPDH gene can be knocked out by homologous recombination. Specific Aim 3 is to determine whethe regions of GAPDH other than the actin-binding domain are important for GAPDH-actin interaction. This will be accomplished by first determining whethe a fusion protein consisting of the entire GAPDH molecule linked to green fluorescent protein colocalizes with actin filaments in prostate cancer cells. Large portions of GAPDH will then be deleted from the fusion protein to determine which regions other than the actin-binding domain, if any, are critical for actin localization.