Diagnostic approach for cancer cells in urine sediments by 5‐aminolevulinic acid‐based photodynamic detection in bladder cancer

Miyake, Makito; Nakai, Yasushi; Anai, Satoshi; Tatsumi, Yoshihiro; Kuwada, Masaomi; Onishi, Sayuri; Chihara, Yoshitomo; Tanaka, Nobumichi; Hirao, Yoshihiko; Fujimoto, Kiyohide

doi:10.1111/cas.12393

Cited by 29 publications

(34 citation statements)

References 17 publications

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“…In the present study, 5‐ALA‐induced fluorescent selective upper tract urinary cytology was more sensitive (90.4%) than conventional selective upper tract urinary cytology (60.3%), regardless of patient age, sex, pT stage and tumor grade. For BT, the same result was attained with 5‐ALA‐induced cytology using voided urine …”

Section: Discussionsupporting

confidence: 63%

High performance of 5‐aminolevulinic acid‐induced fluorescent selective upper tract urinary cytology

Yamamichi¹,

Nakata²,

Yoshimura³

et al. 2020

Int J of Urology

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Objectives To investigate the efficacy of selective upper tract urinary cytology using extracorporeal 5‐aminolevulinic acid for the diagnosis of upper urinary tract urothelial carcinoma. Methods We evaluated 104 patients who underwent radical nephroureterectomy and were diagnosed pathologically as having upper urinary tract urothelial carcinoma between March 2013 and May 2019 in Osaka Rosai Hospital. Preoperatively, we collected upper tract urinary cytology from both sides, and compared the sensitivity and specificity between conventional urine cytology and 5‐aminolevulinic acid‐induced fluorescent urine cytology. Results The sensitivity of 5‐aminolevulinic acid‐induced fluorescent selective upper tract urinary cytology was significantly higher than conventional cytology (90.4% vs 66.3%, P < 0.001), whereas the specificity was equally high (100% vs 98.2%, P = 1.0). In more detailed analysis, the sensitivity of 5‐aminolevulinic acid‐induced fluorescent selective upper tract urinary cytology was significantly higher than that of conventional cytology unrelated to patients’ age (<76 years: 90.2% vs 68.6%, P = 0.013; ≥76 years: 90.6% vs 64.2%, P = 0.021), sex (male: 89.2% vs 67.5%, P = 0.001; female: 95.2% vs 61.9%, P = 0.02) or pT stage (pT1 or less: 91.4% vs 69.0%, P = 0.005; pT2 or more: 89.1% vs 63.0%, P = 0.006), tumor grade (high grade: 91.0% vs 70.5%, P = 0.002; low grade: 88.5% vs 53.8%, P = 0.013), and tended to be more efficacious for tumors that could not be detected by imaging techniques (83.3% vs 50.0%, P = 0.075). Conclusions 5‐Aminolevulinic acid‐induced fluorescent selective upper tract urinary cytology is more sensitive than conventional cytology for the diagnosis of upper urinary tract urothelial carcinoma, regardless of pT stage and tumor grade.

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Section: Discussionsupporting

confidence: 63%

High performance of 5‐aminolevulinic acid‐induced fluorescent selective upper tract urinary cytology

Yamamichi¹,

Nakata²,

Yoshimura³

et al. 2020

Int J of Urology

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“…5‐aminolevulinic acid (ALA) is widely used to induce protoporphyrin IX (PPIX), a photosensitizer used in photodynamic diagnosis and therapy for non‐muscle invasive bladder cancer . ALA is distributed ubiquitously in mammalian cells and is a precursor of tetrapyrole compounds such as heme, which is essential in aerobic energy metabolism and the electron transport system .…”

Section: Introductionmentioning

confidence: 99%

Dual benefit of supplementary oral 5‐aminolevulinic acid to pelvic radiotherapy in a syngenic prostate cancer model

et al. 2018

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Background Normal tissue damage caused by radiotherapy remains the largest dose‐limiting factor in radiotherapy for cancer. Therefore, the aim of this study was to investigate the supplementary oral 5‐aminolevulinic acid (ALA) to standard radiation therapy as a novel radioprotective approach that would not compromise the antitumor effect of radiation in normal rectal and bladder mucosa in a syngenic prostate cancer (PCa) model. Methods To evaluate the radiosensitizing effect of ALA in vitro, clonogenic survival assays were performed in DU145, PC3, and MyC‐CaP cell lines. To evaluate the effect of ALA in vivo a single dose (25 Gy) of radiation with or without ALA was given to healthy mice. Next, a syngenic PCa model of MyC‐CaP cells in FVB mice was created, and multiple doses (12 Gy total) of radiation were administered to the mouse pelvic area with or without ALA administration. Resected tumors, recta, and urinary bladders were immunostained with antibodies against Ki‐67, γ‐H2AX, CD204, and uroplakin‐III. Total RNA levels in recta and urinary bladders were analyzed via RT2 Profiler polymerase chain reaction (PCR) arrays related to “Stress & Toxicity PathwayFinder,” “Mitochondria,” and “Inflammasomes.” Results The addition of in vitro single or in vivo repeated administration of exogenous ALA acted as a radiosensitizer for PCa cells. Rectal toxicity was characterized by histological changes including loss of surface epithelium, fibrosis, severe DNA damage, and the aggregation of M2 macrophages. Urinary bladder toxicity was characterized by bladder wall thickening and urothelium denuding. The higher dose (300 mg/kg/day) of ALA exerted a better radioprotective profile than the lower dose (30 mg/kg/day) in normal recta and urinary bladders. Out of the 252 genes tested, 35 (13.4%) were detected as relevant genes which may be involved in the radioprotective role of ALA administration. These included interleukin‐1a (IL‐1a), IL‐1b, IL‐12, chemokine (C‐X‐C motif) ligand 1 (CXCL1), CXCL3, and NLRP3. Conclusions Our study provides novel and comprehensive insights into the dual benefits including radiosensitizing PCa tumor tissues and radioprotection of normal pelvic organs from radiation therapy. Knowledge of the underlying mechanism will facilitate the search for optimal treatment parameters for supplemental oral ALA during radiotherapy for PCa.

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“…Recently, similar experimental approaches were applied to a clinical trial, that is, directly exposing 5‐ALA to urinary cytology. The results showed that direct 5‐ALA exposure is efficient in discriminating between cancer and noncancer cells …”

Section: Discussionmentioning

confidence: 99%

“…Because of the relatively higher expression of the drug efflux transporter ABCG2 in cancer cells than in noncancer cells, Ko143 was found to alleviate cell‐to‐cell variability in PpIX‐FI. In practice, 5‐ALA combined with ABCG2 inhibitor treatment reduces cell‐to‐cell variability in PpIX‐fluorescence and enhances PpIX accumulation . In contrast, combined administration of 5‐ALA and Ko143 barely altered the PpIX‐FI in the noncancer cells MCF10A expressing low levels of the ABCG2 transporter.…”

Section: Discussionmentioning

confidence: 99%

Fluorescence‐based discrimination of breast cancer cells by direct exposure to 5‐aminolevulinic acid

et al. 2019

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Protoporphyrin IX‐fluorescence measurement is a powerful in situ approach for cancer detection after oral/topical administration of 5‐aminolevulinic acid. However, this approach has not been clinically established for breast cancer, probably due to insufficient delivery of 5‐aminolevulinic acid to the mammary glands. In the present study, we directly exposed breast cancer cells to 5‐aminolevulinic acid to assess their discrimination via protoporphyrin IX‐fluorescence. Fluorescence intensity (FI) was measured in the human breast cancer cell lines MCF7 and MDA‐MB‐231 and breast epithelial cell line MCF10A by confocal microscopy and flow cytometry. After 5‐aminolevulinic acid exposure for 2 hours, protoporphyrin IX‐FI in MCF7 and MDA‐MB‐231 cells significantly increased with marked cell‐to‐cell variability, whereas that in MCF10A cells increased moderately. Combined exposure of the cancer cells to 5‐aminolevulinic acid and Ko143, a specific inhibitor of ATP‐binding cassette transporter G2, further increased protoporphyrin IX‐FI and alleviated the cell‐to‐cell variability in MCF7 and MDA‐MB‐231 cells, indicating improvement in the reproducibility and accuracy for fluorescence‐based cancer detection. The increased FI by combined administration of these two drugs was also demonstrated in cells obtained via fine needle aspiration from mouse xenograft models inoculated with MDA‐MB‐231 cells. Furthermore, a cutoff value for increased protoporphyrin IX‐FI ratio, before and after exposure to these drugs, clearly discriminated between cancer and noncancer cells. Taken together, direct exposure to 5‐aminolevulinic acid and Ko143 may be a promising strategy for efficient fluorescence‐based detection of breast cancer cells ex vivo using fine needle aspiration.

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Diagnostic approach for cancer cells in urine sediments by 5‐aminolevulinic acid‐based photodynamic detection in bladder cancer

Cited by 29 publications

References 17 publications

High performance of 5‐aminolevulinic acid‐induced fluorescent selective upper tract urinary cytology

High performance of 5‐aminolevulinic acid‐induced fluorescent selective upper tract urinary cytology

Dual benefit of supplementary oral 5‐aminolevulinic acid to pelvic radiotherapy in a syngenic prostate cancer model

Fluorescence‐based discrimination of breast cancer cells by direct exposure to 5‐aminolevulinic acid

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