Pharmacologic Inhibition of Amino Acid Metabolism
The hypothesis that selective amino acid deprivation inhibits tumor growth is also being evaluated through the pharmacologic inhibition of specific amino acid metabolism.9 Multiple drugs have been developed and are in preclinical to phase 2 studies that target specific enzymatic steps in the metabolism of amino acids such as arginine, tryptophan, serine, glycine, glutamine, and leucine, isoleucine, and valine.
For example, several clinical trials are evaluating arginine deiminase (ADI-PEG20), which depletes arginine. A phase 3 trial of patients with advanced hepatocellular carcinoma, however, found no difference in overall survival or progression-free survival compared with placebo.10 Other trials are ongoing that are evaluating arginine deiminase in other cancer types and in combination with other therapies.11
In vitro and in vivo data suggest that selective amino acid deprivation may have anticancer activity; agents that inhibit select amino acid metabolism are being developed as anticancer therapy. The CAAT protocol, however, has not been formally evaluated in preclinical or clinical studies.
Though some components of the CAAT protocol have been studied, few have shown efficacy in clinical trials. There are insufficient data to suggest that the CAAT protocol is an effective treatment for cancer.
- Therapy offers hope for cancer sufferers [news release]. Jacksonville, FL: Market Wired; November 16, 2005. http://www.marketwired.com/press-release/therapy-offers-hope-for-cancer-sufferers-670868.htm. Accessed April 9, 2018.
- Controlled amino acid therapy (CAAT) part #5 protocol for physicians. Natural Solutions Radio website. http://naturalsolutionsradio.com/blog/natural-solutions-radio/controlled-amino-acid-therapy-caat-part-5-protocol-physicians. Published October 4, 2003. Accessed April 9, 2018.
- López-Lázaro M. Selective amino acid restriction therapy (SAART): a nonpharmacological strategy against all types of cancer cells. Oncoscience. 2015;2:857-67.
- Fontana L, Adelaiye RM, Rastelli AL, et al. Dietary protein restriction inhibits tumor growth in human xenograft models of prostate and breast cancer. Oncotarget. 2013;4:2451-62.
- Saito Y, Moriya S, Kazama H, et al. Amino acid starvation culture condition sensitizes EGFR-expressing cancer cell lines to gefitinib-mediated cytotoxicity by inducing atypical necroptosis. Int J Oncol. 2018;52:1165-77. doi: 10.3892/ijo.2018.4282
- Maddocks ODK, Athineos D, Cheung EC, et al. Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature. 2017;544:373-6. doi: 10.1038/nature22056
- Lorincz AB, Kuttner RE, Brandt MB. Tumor response to phenylalanine-tyrosine-limited diets. J Am Diet Assoc. 1969;54(3):198-205.
- Demopoulos HB. Effects of reducing the phenylalanine-tyrosine intake of patients with advanced malignant melanoma. Cancer. 1966;19:657-65.
- Ananieva E. Targeting amino acid metabolism in cancer growth and anti-tumor immune response. World J Biol Chem. 2015;26:281-9. doi: 10.4331/wjbc.v6.i4.281
- Abou-Alfa GK, Qin S, Ryo BY, et al. Phase III randomized study of second line ADI-peg 20 (A) plus best supportive care versus placebo (P) plus best supportive care in patients (pts) with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2016;34(suppl):4017.
- Tsai HJ, Jiang SS, Hung WC, et al. A phase II study of arginine deiminase (ADI-PEG20) in relapsed/refractory or poor-risk acute myeloid leukemia patients. Sci Rep. 2017;7:11253-63. doi: 10.1038/s41598-017-10542-4