δ-Aminolevulinic acid (alsodALA,δ-ALA,5ALA, 5-ALA or5-aminolevulinic acid), an endogenousnon-proteinogenic amino acid, is the first compound in theporphyrin synthesis pathway, the pathway that leads toheme[3] in mammals, as well aschlorophyll[4] in plants.
5-ALA is used in photodynamic detection and surgery of cancer.[5][6][7][8]
As a precursor of a photosensitizer, 5-ALA is also used as an add-on agent forphotodynamic therapy.[9] In contrast to larger photosensitizer molecules, it is predicted by computer simulations to be able to penetrate tumor cell membranes.[10]
Photodynamic detection is the use of photosensitive drugs with a light source of the right wavelength for the detection of cancer, using fluorescence of the drug.[5] 5-ALA, or derivatives thereof, can be used to visualize bladder cancer by fluorescence imaging.[5]
Aminolevulinic acid is being studied forphotodynamic therapy (PDT) in a number of types of cancer.[11] It is not currently a first line treatment forBarrett's esophagus.[12] Its use inbrain cancer is currently experimental.[13] It has been studied in a number of gynecological cancers.[14]
Aminolevulinic acid utilization is promising in the field of cancer delineation, particularly in the context offluorescence-guided surgery. This compound is utilized to enhance the visualization ofmalignant tissues during surgical procedures.[7][8] TheUS FDA approved aminolevulinic acid hydrochloride (ALA HCL) for this use in 2017.[15]
When administered to patients, 5-ALA is metabolized toprotoporphyrin IX (PpIX) preferentially in cancer cells, leading to theirfluorescence under specificlight wavelengths.[16] This fluorescence aids surgeons in real-time identification and precise removal of cancerous tissue, reducing the likelihood of leaving residual tumor cells behind. This innovative approach has shown success in various cancer types, includingbrain and spinegliomas,bladder cancer, andoral squamous cell carcinoma.[17][18][19]
Aminolevulinic acid is indicated in adults for visualization of malignant tissue during surgery for malignant glioma (World Health Organization grade III and IV).[20]
Studies since 2006 have shown that the intraoperative use of this guiding method may reduce the tumour residual volume and prolongprogression-free survival in people withmalignant gliomas.[7][8]
Cytoreductive surgery has been considered to be benficial for patients with high-grade-gliomas;[21] it has resulted in significantly higher rate of complete resections in malignant gliomas, compared to the traditional white-light resections. The use of 5-ALA has been described as an essential technique, and as standard-of-care at many neurosurgical departments worldwide.[22]
In non-photosynthetic eukaryotes such as animals, fungi, and protozoa, as well as the classAlphaproteobacteria of bacteria, it is produced by the enzymeALA synthase, fromglycine andsuccinyl-CoA. This reaction is known as the Shemin pathway, which occurs in mitochondria.[23]
In plants, algae, bacteria (except for the class Alphaproteobacteria) and archaea, it is produced from glutamic acid via glutamyl-tRNA and glutamate-1-semialdehyde. The enzymes involved in this pathway are glutamyl-tRNA synthetase,glutamyl-tRNA reductase, andglutamate-1-semialdehyde 2,1-aminomutase. This pathway is known as the C5 or Beale pathway.[24][25] In most plastid-containing species, glutamyl-tRNA is encoded by a plastid gene, and the transcription, as well as the following steps of C5 pathway, take place in plastids.[26]
In humans, 5ALA is a precursor toheme.[3] Biosynthesized 5ALA goes through a series of transformations in thecytosol, finally being converted toprotoporphyrin IX inside themitochondria.[27][28] This protoporphyrin molecule chelates with iron in presence of enzymeferrochelatase to produceheme.[27][28]
Cancer cells lack or have reduced ferrochelatase activity and this results in accumulation of protoporphyrin IX, afluorescent substance that can easily be visualized.[5]
In plants, production of 5-ALA is the step on which the speed of synthesis ofchlorophyll is regulated.[4] Plants that are fed by external 5-ALA accumulate toxic amounts of chlorophyll precursor,protochlorophyllide, indicating that the synthesis of this intermediate is not suppressed anywhere downwards in the chain of reaction. Protochlorophyllide is a strong photosensitizer in plants.[31] Controlled spraying of 5-ALA at lower doses (up to 150 mg/L) can however help protect plants from stress and encourage growth.[32]
^abcdWagnières, G.., Jichlinski, P., Lange, N., Kucera, P., Van den Bergh, H. (2014). Detection of Bladder Cancer by Fluorescence Cystoscopy: From Bench to Bedside - the Hexvix Story. Handbook of Photomedicine, 411-426.
^Eyüpoglu IY, Buchfelder M, Savaskan NE (March 2013). "Surgical resection of malignant gliomas-role in optimizing patient outcome".Nature Reviews. Neurology.9 (3):141–151.doi:10.1038/nrneurol.2012.279.PMID23358480.S2CID20352840.
^abcStummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ (May 2006). "Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial".The Lancet. Oncology.7 (5):392–401.doi:10.1016/s1470-2045(06)70665-9.PMID16648043.
^Yew YW, Lai YC, Lim YL, Chong WS, Theng C (June 2016). "Photodynamic Therapy With Topical 5% 5-Aminolevulinic Acid for the Treatment of Truncal Acne in Asian Patients".Journal of Drugs in Dermatology.15 (6):727–732.PMID27272080.
^abTetard MC, Vermandel M, Mordon S, Lejeune JP, Reyns N (September 2014). "Experimental use of photodynamic therapy in high grade gliomas: a review focused on 5-aminolevulinic acid".Photodiagnosis and Photodynamic Therapy.11 (3):319–330.doi:10.1016/j.pdpdt.2014.04.004.PMID24905843.S2CID38534019.
^Albalkhi I, Shafqat A, Bin-Alamer O, Abou Al-Shaar AR, Mallela AN, Fernández-de Thomas RJ, et al. (December 2023). "Fluorescence-guided resection of intradural spinal tumors: a systematic review and meta-analysis".Neurosurgical Review.47 (1) 10.doi:10.1007/s10143-023-02230-x.PMID38085385.S2CID266164983.
^Filip P, Lerner DK, Kominsky E, Schupper A, Liu K, Khan NM, et al. (February 2024). "5-Aminolevulinic Acid Fluorescence-Guided Surgery in Head and Neck Squamous Cell Carcinoma".The Laryngoscope.134 (2):741–748.doi:10.1002/lary.30910.PMID37540051.S2CID260485667.
^Ewelt C, Nemes A, Senner V, Wölfer J, Brokinkel B, Stummer W, et al. (July 2015). "Fluorescence in neurosurgery: Its diagnostic and therapeutic use. Review of the literature".Journal of Photochemistry and Photobiology. B, Biology.148:302–309.Bibcode:2015JPPB..148..302E.doi:10.1016/j.jphotobiol.2015.05.002.PMID26000742.
^Willows RD (2004). "Chlorophylls". In Goodman RM (ed.).Encyclopaedia of Plant and Crop Science. Marcel Dekker. pp. 258–262.ISBN0-8247-4268-0.
^Biswal B, Krupinska K, Biswal UC, eds. (July 2013).Plastid development in leaves during growth and senescence. Dordrecht, The Netherlands: Springer.ISBN9789400757233.
^abMalik Z, Djaldetti M (June 1979). "5-Aminolevulinic acid stimulation of porphyrin and hemoglobin synthesis by uninduced Friend erythroleukemic cells".Cell Differentiation.8 (3):223–233.doi:10.1016/0045-6039(79)90049-6.PMID288514.
