Plasma protoporphyrin IX following administration of 5-aminolevulinic acid as a potential tumor marker

Ota, Urara; Fukuhara, Hideo; Ishizuka, Masahiro; Abe, Fuminori; Kawada, Chiaki; Takagi, Kenji; Tanaka, Tohru; Inoue, Keiji; Ogura, Shun‐ichiro; Shuin, Taro

doi:10.3892/mco.2015.549

Cited by 15 publications

(18 citation statements)

References 10 publications

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“…Treatment with 5-aminolevulinic acid (5-ALA) results in progressive accumulation of PpIX in malignant tissue but not in the surrounding tissue, thus offering a means of distinguishing healthy from pathological tissues, exploiting the fluorescence properties of PpIX [ 29 ]. Several studies have demonstrated the broad applicability in cancer detection of fluorescence analysis of intrinsic or stimulated PpIX, on samples of ex vivo tissue and biofluids in which the PpIX may pour out of the tumor cells [ 21 – 25 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…Several studies suggest that tumor cells are able to produce porphyrins naturally or after administering their precursor [ 13 , 21 – 23 ] and that porphyrin compounds are responsible for plasma red fluorescence [ 24 , 25 ]. On this basis, we assumed that the difference between the blood fluorescence spectra of colorectal adenocarcinoma patients and control subjects was due to endogenous porphyrins accumulated in cancer cells as a result of a systemic alteration of heme metabolism, and then pumped out to plasma.…”

Section: Methodsmentioning

confidence: 99%

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Early detection of colorectal adenocarcinoma: a clinical decision support tool based on plasma porphyrin accumulation and risk factors

et al. 2018

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BackgroundAn increase in naturally-occurring porphyrins has been described in the blood of subjects bearing different kinds of tumors, including colorectal, and this is probably related to a systemic alteration of heme metabolism induced by tumor cells. The aim of our study was to develop an artificial neural network (ANN) classifier for early detection of colorectal adenocarcinoma based on plasma porphyrin accumulation and risk factors.MethodsWe measured the endogenous fluorescence of blood plasma in 100 colorectal adenocarcinoma patients and 112 controls using a conventional spectrofluorometer. Height, weight, personal and family medical history, use of alcohol, red meat, vegetables and tobacco were all recorded. An ANN model was built up from demographic data and from the integral of the fluorescence emission peak in the range 610–650 nm. We used the Receiver Operating Characteristic (ROC) curve to assess performance in distinguishing colorectal adenocarcinoma patients and controls. A liquid chromatography-high resolution mass spectrometry (LC-HRMS) analytical method was employed to identify the agents responsible for native fluorescence.ResultsThe fluorescence analysis indicated that the integral of the fluorescence emission peak in the range 610–650 nm was significantly higher in colorectal adenocarcinoma patients than controls (p < 0.0001) and was weakly correlated with the TNM staging (Spearman’s rho = 0.224, p = 0.011). LC-HRMS measurements showed that the agents responsible for the fluorescence emission were mainly protoporphyrin-IX (PpIX) and coproporphyrin-I (CpI). The overall accuracy of our ANN model was 88% (87% sensitivity and 90% specificity) with an area under the ROC curve of 0.83.ConclusionsThese results confirm that tumor cells accumulate a diagnostic level of endogenous porphyrin compounds and suggest that plasma porphyrin concentrations, indirectly measured through fluorescence analysis, may be useful, together with risk factors, as a clinical decision support tool for the early detection of colorectal adenocarcinoma. Our future efforts will be aimed at examining how plasma porphyrin accumulation correlates with survival and response to therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Early detection of colorectal adenocarcinoma: a clinical decision support tool based on plasma porphyrin accumulation and risk factors

et al. 2018

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“…It isolates the analyte from the sample matrix and concentrates it. Conclusively, the application of high-performance liquid chromatography (HPLC) coupled with fluorescence detection (FLD, UV-visible detection was not sensitive enough) [30,[32][33][34][35][36][37] and MS became highly popular. Initially performed thin layer chromatography assays were gradually replaced in the 1980s [36].…”

Section: Liquid Chromatographymentioning

confidence: 99%

“…More recently, besides the analysis of porphyrin metabolites [39] and profiles for toxicological and pharmacological applications [40][41][42], PPIX has been investigated as tumor marker for bladder, colorectal and kidney cancer [10,11,32]. Tumor cells are able to produce porphyrins naturally or after administration of ALA, which is also reflected in elevated plasma fluorescence of cancer patients.…”

Section: Protoporphyrin Ix: a Potential Biomarker For Cancer Screeningmentioning

confidence: 99%

Protoporphyrin IX Analysis from Blood and Serum in the Context of Neurosurgery of Glioblastoma

Walke¹,

Molina²,

Stummer³

et al. 2021

Mass Spectrometry in Life Sciences and Clinical Laboratory

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Protoporphyrin IX (PPIX) is formed from δ-aminolevulinic acid (ALA) during heme biosynthesis. Due to its cyclic tetrapyrrole core structure, it absorbs in the visible region of the electromagnetic spectrum and is thus colored. Both ALA and PPIX have become of great interest to neurosurgery, because in high-grade glioma, ALA diffuses into the tumor and is converted to PPIX. Fluorescence-guided resection (FGR) takes advantage of both the enrichment of PPIX in the tumor and its fluorescent properties, which enable visualization of tumor tissue. ALA-mediated FGR thus maximizes the extent of resection with better prognosis for patients. Tumor cells are able to produce porphyrins naturally or after administration of ALA, which is also reflected in elevated plasma fluorescence of cancer patients. PPIX might thus serve as a biomarker for monitoring of the tumor burden. A liquid chromatography-mass spectrometry (LC-MS)-based method is presented to quantify PPIX in blood and serum in the context of current fluorescence-based diagnostics. The method is able to distinguish between zinc PPIX, a component of red blood cells of importance in the detection of lead poisoning and iron deficiency anemia, and metal-free PPIX. In a proof-of-principle study, it was used to follow a time course of a glioblastoma patient undergoing surgery and confirmed elevated PPIX blood levels before ALA administration. During surgery, these blood levels increased about four-fold. The here developed 10 min reversed-phase LC-target MS method now allows patient screening with high specificity and throughput.

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“…Blood ALA and its metabolites were measured at 9 time points during the 8 h after the first ALA dose, according to Ota et al . in the setting of ALA 180 mg twice per day.…”

mentioning

confidence: 99%

Five‐aminolevulinic acid: New approach for congenital sideroblastic anemia

Ishida

Imamura

Morimoto

et al. 2018

Pediatrics International

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Plasma protoporphyrin IX following administration of 5-aminolevulinic acid as a potential tumor marker

Cited by 15 publications

References 10 publications

Early detection of colorectal adenocarcinoma: a clinical decision support tool based on plasma porphyrin accumulation and risk factors

Early detection of colorectal adenocarcinoma: a clinical decision support tool based on plasma porphyrin accumulation and risk factors

Protoporphyrin IX Analysis from Blood and Serum in the Context of Neurosurgery of Glioblastoma

Five‐aminolevulinic acid: New approach for congenital sideroblastic anemia

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