Real-world prostate-specific antigen response and progression to castration-resistant prostate cancer among men with metastatic castration-sensitive prostate cancer treated with apalutamide: a multi-institutional study in the Chu-shikoku Japan Urological Consortium.

BACKGROUND: Japanese men receiving apalutamide often experience skin-adverse events (AEs), possibly requiring treatment interruption or dose reduction. However, concerns have arisen regarding the impact of these adjustments on the efficacy of apalutamide. Our study evaluated the efficacy, safety, and persistence of apalutamide in men with metastatic castration-sensitive prostate cancer (mCSPC). METHODS: We retrospectively reviewed the medical records of 108 men with mCSPC from 14 Japanese institutions. The primary outcomes were the efficacy of apalutamide: prostate-specific antigen (PSA) response (50%, 90% and < 0.2 decline) and progression to castration-resistant prostate cancer (CRPC). The secondary outcomes were the skin-AE and compliance of apalutamide. RESULTS: PSA50%, PSA90% and PSA < 0.2 declines were observed in 89.8, 84.3 and 65.7%, and the median time to CRPC progression was not reached. PSA < 0.2 decline and an initial full dose of apalutamide were significantly associated with a longer time to CRPC. The most common AE was skin-AE (50.9%), and there was no association between the occurrence of skin-AE and the time to CRPC (P = 0.72). The median apalutamide persistence was 29 months, which was longer in the initial full dose recipients than in the reduced dose recipients. The dosage is reduced in about 60% of patients within the first year of treatment in the initial full dose recipients. CONCLUSIONS: Our findings indicate the effectiveness of apalutamide in Japanese men with mCSPC, despite a substantial portion requiring dose reduction within a year among the initial full dose recipients.

Current status of photodynamic technology for urothelial cancer.

5-Aminolevulinic acid is a new-generation photosensitizer with high tumor specificity. It has been used successfully in the diagnosis, treatment, and screening of urological cancers including bladder cancer; specifically, it has been used in photodynamic diagnosis to detect tumors by illuminating the lesion with a specific wavelength of light to produce fluorescence in the lesion after administration of 5-aminolevulinic acid, in photodynamic therapy, which induces tumor cell death via production of cytotoxic reactive oxygen species, and in photodynamic screening, in which porphyrin excretion in the blood and urine is used as a tumor biomarker after administration of 5-aminolevulinic acid. In addition to these applications in urological cancers, 5-aminolevulinic acid-based photodynamic technology is expected to be used as a novel strategy for a large number of cancer types because it is based on a property of cancer cells known as the Warburg effect, which is a basic biological property that is common across all cancers.

Sarcopenia and the rate of change of the neutrophil/lymphocyte ratio as predictors of pembrolizumab efficacy in advanced urothelial carcinoma.

The objective was to evaluate the usefulness of sarcopenia and the neutrophil/lymphocyte ratio (NLR) as therapeutic efficacy predictors in patients who received pembrolizumab after platinum-based chemotherapy for advanced urothelial carcinoma (aUC). Forty-four patients with aUC were enrolled. Patients' background characteristics and clinical factors, the skeletal muscle index, and the psoas muscle index were evaluated. The NLR before and during treatment was calculated, and the rate of change of NLR was calculated. The median age was 70 years; the follow-up period was 13.2 months. The response rate was 54%. The nonresponding group had significantly more sarcopenia cases (P = 0.007) and a high rate of change of NLR (P = 0.0076). Progression-free survival (PFS) was significantly shorter in the group with sarcopenia (P = 0.002). Both PFS and overall survival were significantly shorter with an NLR rate of change greater than or equal to 1 (P = 0.001 and P = 0.002). On multivariate analysis, the presence of immune-related adverse events [hazard ratio (HR), 0.3723; 95% confidence interval (CI), 0.14-0.97; P = 0.04] and the NLR rate of change (HR, 3.986; 95% CI, 1.01-15.70; P = 0.048) were independent predictors of PFS. Sarcopenia and the rate of change of NLR appear to be useful as predictors of pembrolizumab efficacy in aUC.

Photodynamic diagnosis and therapy for urothelial carcinoma and prostate cancer: new imaging technology and therapy.

Photodynamic technology using light-sensitive and fluorescent substances has an important role in an accurate diagnosis for a variety of malignancies, including bladder cancer and prostate cancer. Light-sensitive and fluorescent substances accumulate specifically in tumor cells compared to normal tissue, and by light irradiation and excitation at each specific wavelength, tumor lesion, blood flow, lymph node and so on show fluorescence. 5-Aminolevulinic acid (ALA) is converted to protoporphyrin IX (PpIX) into mitochondria. PpIX is excited by blue light, red fluorescence is emitted in the mitochondria. This phenomenon is the mechanism of ALA-mediated photodynamic diagnosis (ALA-PDD). ALA-PDD has made it possible to visualize smaller lesions and flat lesions that were previously difficult to visualize by endoscope using a white-light source. So accurate diagnosis and complete resection become possible during operation. The accumulation of PpIX in the mitochondria also induces direct mitochondrial damage and subsequent cell death by red and green light. This biological reaction is the ALA-mediate photodynamic therapy (ALA-PDT). ALA-PDT has been developed as a modality for minimum invasive cancer treatment that utilizes low-energy light and photosensitizer. Vascular-activated photosensitizer induces rapid tumor ablation by PDT involving direct tumor cell killing as well as damage to the exposed microvasculature. We summarize the clinical outcomes of PDD and PDT for urothelial carcinoma and prostate cancer.

Effects of percutaneous cryoablation for renal tumor on overall and split renal function.

PURPOSE: To evaluate retrospectively the influence of percutaneous cryoablation for small renal tumors on total and affected kidney function and risk factors associated with worsening function of the affected kidney. MATERIALS AND METHODS: Between April 2016 and March 2022, 27 patients who underwent cryoablation for small renal tumors at our institution participated in this study, which investigated time-dependent changes in postoperative renal function. We evaluated estimated glomerular filtration rates (eGFRs) and split renal function revealed by scintigraphy using 99 m technetium-mercaptoacetyltriglycine (99mTc-MAG3) before cryoablation and at 1 week, 1 month, and 6 months after cryoablation. Numerous variables were analyzed to assess risk factors for worsening renal function. RESULTS: Baseline eGFR (mean ± standard deviation) was 56.5 ± 23.7 mL/min/1.73 m2 (mean ± SD; range, 20.5-112.5). Mean eGFRs at 1 week, 1 month, and 6 months after cryoablation were 57.4 ± 24.5 (19.1-114.9), 57.1 ± 25.1 (21.5-114.9), and 53.8 ± 23.9 mL/min/1.73 m2 (20.0-107.5), respectively. Changes were statistically insignificant (p = 1.0000, = 0.6749, and = 0.0761, respectively). Regarding split renal function, mean baseline contribution of the affected kidney determined by 99mTc-MAG3 was 49.7% ± 6.0% (38.8-63.3%); these rates at 1 week, 1 month, and 6 months after cryoablation were 43.7% ± 8.8 (29.1-70.6%), 46.2% ± 7.7% (32.6-70.3%), and 46.0% ± 8.5% (32.5-67.6%), respectively. Differences from baseline were significant for all periods (p < 0001, < 0001, = 0.0001, respectively). Serum C reactive protein and lactate dehydrogenase at 1 day following cryoablation, tumor's nearness to the collecting system or sinus, and volume of ablated normal renal parenchyma were significantly correlated with decreased contributions of the affected kidney by > 10% after cryoablation. CONCLUSION: Unlike total renal function, affected kidney function could worsen after cryoablation.

A new method for effective use of the ClearPetra ureteral access sheath for a giant ureteral stone.

The ClearPetra (Well Lead Medical, Guangzhou, China) has recently entered the market, enabling continuous stone fragmentation and removal while maintaining a continuous perfusion field of view. The efficacy and safety of the ClearPetra renal access sheath (RAS) in percutaneous nephrolithotomy (PCNL) and endoscopic combined intrarenal surgery (ECIRS) have been reported. However, no reports have described the use of the ClearPetra ureteral access sheath (UAS). Here, we report a case of successful ureteroscopic lithotripsy (URSL) for a giant ureteral stone by effectively utilizing the ClearPetra UAS.

Cell senescence-associated porphyrin metabolism affects the efficacy of aminolevulinic acid-photodynamic diagnosis in bladder cancer.

Aminolevulinic acid-photodynamic diagnosis (ALA-PDD) is a promising alternative method to detect cancer cells because of its high specificity and low rate of side effects. Exogenous ALA is administered and accumulates as protoporphyrin IX (PpIX) in cancer cells, which then emit red fluorescence following light irradiation to enable surgeons to accurately identify and remove cancerous tissue. Recent reports suggested that PpIX failed to accumulate in some patients who underwent ALA-PDD. We hypothesized that cell senescence, which is a relatively inactive state, affects porphyrin accumulation in bladder cancer cells. In this study, we evaluated the relationship between cell senescence and porphyrin accumulation in affecting the efficacy of ALA-PDD. First, we utilized three bladder cancer cell lines to evaluate senescence-related indicators and establish a cell senescence model. Then, we identified the differences in porphyrin production and the proteins involved in porphyrin accumulation between old and young cells. We found that compared with young cells, old cells possessed higher concentration of PpIX and had lower ABCG2 expression. The increase in PpIX levels following ABCG2 inhibition is three times higher in old cells than in young cells, suggesting that cell senescence was closely related with porphyrin accumulation in cancer. In conclusion, we found that the efficacy of ALA-PDD and porphyrin accumulation was relatively high in senescent cancer cells and that inhibition of ABCG2 could improve the efficacy of ALA-PDD in young bladder cancer cells.

Mangostin enhances efficacy of aminolevulinic acid-photodynamic therapy against cancer through inhibition of ABCG2 activity.

BACKGROUND: Aminolevulinic acid-photodynamic therapy (ALA-PDT) is gaining attention as a potential method for treating select cancers due to its high specificity and low side effect feature. ALA enters cancer cells and accumulate as protoporphyrin IX (PpIX), which will then trigger phototoxicity following light irradiation. However, it is reported that some cancer cells have reduced efficacy of ALA-PDT due to high expression of ABCG2, a transporter involved in the PpIX efflux. In this study, we evaluated the effect of mangostin, a natural compound containing anti-tumor property, on the efficacy of ALA-PDT against cancer and the mechanism involved. METHODS: We utilized TMK1 gastric cancer cell line, which has high ABCG2 expression, to evaluate the PpIX accumulation and phototoxicity exerted by ALA and mangostin co-addition. RESULTS: We found that co-addition of ALA and mangostin significantly increase the phototoxicity and PpIX accumulation in TMK1 cells. We also investigated the effect of mangostin on porphyrin-heme pathway enzymes and ABCG2 and found that the addition of mangostin reduce the activity of ABCG2, reducing PpIX efflux. CONCLUSION: These findings suggest that mangostin enhances the efficacy of ALA-PDT in cancer through inhibition of ABCG2 activity.

Metabolic shift towards oxidative phosphorylation reduces cell-density-induced cancer-stem-cell-like characteristics in prostate cancer in vitro.

Numerous cancer patients undergoing conventional cancer therapies such as radiotherapy, chemotherapy and surgical tumour removal face relapses several years or even decades later. This may be due to the presence of cancer stem cells (CSCs) that survived said therapies. In this study, we aimed to uncover the relationship between cell density and CSCs, and the role of the Warburg effect in regulating CSC-like characteristics. A prostate cancer cell line, PC3, was used in this study. To investigate the Warburg effect effect and CSC-like characteristics in prostate cancer, we measured the expression levels of glycolysis and OXPHOS-related genes, and performed spheroid forming, cell viability and various glycolysis and OXPHOS-assays. We observed that increased cell density caused a metabolic shift from glycolysis to OXPHOS and higher CSC-like characteristics. However, the use of dichloroacetate (DCA), an inhibitor of the Warburg effect, significantly inhibited the cell-density-induced metabolic shift and CSC-like characteristics. Changes in cell density strongly influenced the preferred metabolic pathway of prostate cancer cells, regulating their CSC-like characteristics. It is possible that DCA, an inhibitor of the Warburg effect, could be a novel drug used to treat CSCs by distinguishing Warburg effect, preventing future cancer relapses.

Real-world experience with 5-aminolevulinic acid for photodynamic diagnosis of bladder cancer (2nd report): Reduced bladder recurrence after PDD-TURBT.

BACKGROUND: Photodynamic diagnosis (PDD) with administration of oral aminolevulinic acid (ALA) prior to transurethral resection of bladder tumor (TURBT) can now be used for non-muscle invasive bladder cancer (NMIBC) in clinical settings in Japan. Since ALA was first marketed, a limited number of reports have described PDD-TURBT outcomes, and the effects of resecting false-positive tissue on outcomes have not been clarified. METHODS: This study compared tumor recurrence among NMIBC patients who underwent TURBT under either white light cystoscopy (WL) or PDD. In addition, the frequency of recurrence was compared between patients with or without false-positive lesions at the time of PDD-TURBT. RESULTS: The frequency of recurrence in NMIBC patients (cumulative number of recurrences/cumulative number of follow-up days, number of recurrences/10,000 days), including progression to muscle-invasive bladder cancer (MIBC), was 12.80 in the WL-TURBT group and 5.82 in the PDD-TURBT group (p < 0.05). Tumor recurrence after TURBT was seen in 29 of 88 patients (33.0%) in the WL-TURBT group and 21 of 105 patients (20.0%) in the PDD-TURBT group (p < 0.05). Mean (± standard deviation) time to first recurrence was 249 ± 140 days in the WL-TURBT group and 419 ± 219 days in the PDD-TURBT group (p < 0.05). The frequency of recurrence in PDD-TURBT-group NMIBC patients was significantly lower in patients with resection of false-positive tissue (4.19/10,000 days) than in those without (9.00/10,000 days, p < 0.05). CONCLUSION: The frequency of recurrence was lower and the time to recurrence was longer in the PDD-TURBT group than in the WL-TURBT group. The frequency of recurrence decreased with resection of false-positive resection.

Synthesis and photophysical properties of a new push-pull pyrene dye with green-to-far-red emission and its application to human cellular and skin tissue imaging.

Herein, we discuss a new pyrene-based push-pull dye (PC) and our investigation of its photophysical properties and applicability to biological studies. The newly synthesized dye exhibits highly polarity-sensitive fluorescence over a significantly wide range (i.e., the green to far-red region), accompanied by high fluorescence quantum yields (ΦFL > 0.70 in most organic solvents) and superior photostability to that of the commonly used Nile Red (NR) dye, which also fluoresces in the green to red region. When human prostate cancer cells stained with PC were imaged using a confocal laser scanning fluorescence microscope, PC was found to selectively stain the lipid droplets. Under the cell conditions where the formation of droplets was inhibited, PC could be distributed to both the remaining droplets and the intercellular membranes, which could be distinguished based on the fluorescence solvatochromic function of PC. Furthermore, PC efficiently stained normal human skin tissue blocks treated with a transparency-enhancing agent and enabled clear visualization of individual cells in each tissue architecture by means of two-photon fluorescence microscopy (2PM). Interestingly, PC provides bright 2PM images under tissue-penetrative 960 nm excitation, realizing much clearer and deeper tissue imaging than conventional pyrene dyes and NR. These results suggest that PC could replace several commonly used dyes in various biological applications, particularly the rapid and accurate diagnosis of tissue diseases, typified by biopsy.

Association of 5-aminolevulinic acid with intraoperative hypotension in malignant glioma surgery.

BACKGROUND: Use of 5-aminolevulinic acid for photodynamic malignant tumor diagnosis reportedly causes intraoperative hypotension (systolic blood pressure < 70 mmHg) during urologic surgery. However, its association with intraoperative hypotension in malignant glioma surgery and underlying mechanisms has not yet been elucidated.. This study aimed to investigate whether 5-aminolevulinic acid administration is associated with intraoperative hypotension in malignant glioma surgery and explore the mechanisms of 5-aminolevulinic acid-induced hypotension in vitro. METHODS: In this retrospective multicenter cohort study, we investigated intracellular nitric oxide as a candidate mediator of hypotension in response to 5-aminolevulinic acid in vitro in human umbilical vein endothelial cell cultures. RESULTS: Of 142 patients, 94 underwent 5-aminolevulinic acid-guided surgery. Systolic blood pressure was significantly lower throughout surgery with 5-aminolevulinic acid administration. 5-Aminolevulinic acid administration was an independent risk factor for intraoperative hypotension according to multivariable logistic regression analysis (89% vs. 56%; odds ratio = 6.72, 95% confidence interval [2.05-22.1], P = 002). In subgroup analysis of the 5-aminolevulinic acid group, increasing age and use of renin-angiotensin system inhibitors had a synergistic effect with 5-aminolevulinic acid on decreased blood pressure. In the vascular endothelial cell culture study, 5-aminolevulinic acid induced a significant increase in intracellular nitric oxide generation. CONCLUSIONS: 5-Aminolevulinic acid administration was associated with intraoperative hypotension in malignant glioma surgery, with increasing age and use of renin-angiotensin system inhibitors boosting the blood pressure-lowering effect of 5-aminolevulinic acid. According to in vitro results, the low blood pressure induced by 5-aminolevulinic acid may be mediated by a nitric oxide increase in vascular endothelial cells.

Enhanced lipid metabolism induces the sensitivity of dormant cancer cells to 5-aminolevulinic acid-based photodynamic therapy.

Cancer can develop into a recurrent metastatic disease with latency periods of years to decades. Dormant cancer cells, which represent a major cause of recurrent cancer, are relatively insensitive to most chemotherapeutic drugs and radiation. We previously demonstrated that cancer cells exhibited dormancy in a cell density-dependent manner. Dormant cancer cells exhibited increased porphyrin metabolism and sensitivity to 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT). However, the metabolic changes in dormant cancer cells or the factors that enhance porphyrin metabolism have not been fully clarified. In this study, we revealed that lipid metabolism was increased in dormant cancer cells, leading to ALA-PDT sensitivity. We performed microarray analysis in non-dormant and dormant cancer cells and revealed that lipid metabolism was remarkably enhanced in dormant cancer cells. In addition, triacsin C, a potent inhibitor of acyl-CoA synthetases (ACSs), reduced protoporphyrin IX (PpIX) accumulation and decreased ALA-PDT sensitivity. We demonstrated that lipid metabolism including ACS expression was positively associated with PpIX accumulation. This research suggested that the enhancement of lipid metabolism in cancer cells induces PpIX accumulation and ALA-PDT sensitivity.

Sunitinib with photoirradiation-mediated reactive oxygen species generation induces apoptosis of renal cell carcinoma cells.

BACKGROUND: Photodynamic therapy is a clinically approved, minimally invasive,therapeutic procedure used for the treatment of several cancers. In recent years, sunitinib, one of the tyrosine kinase inhibitors, has also attracted attention as a novel photosensitizer. However, there is currently no data available on the combined cytotoxic effects of sunitinib and photoirradiation on renal cell carcinoma including how the treatment induced cellular toxicity. METHODS: In the present study, we used sunitinib as a photosensitizer and evaluated the effects of sunitinib and photodynamic therapy treatment on renal cancer cell lines, including the induction of cell death. RESULTS: Our study showed that treatment with sunitinib and photoirradiation at 8 mW/cm2 for 30 min resulted in the production intracellular reactive oxygen species (ROS), which is indicated by the increase in mRNA expression levels of PAI-1, NF-κß, and Caspase-3. An increase in rate of apoptotic reaction and increase in the expression level of apoptotic marker were also observed when cells undergo treatment with sunitinib and photoirradiation. CONCLUSIONS: Our findings suggest that combining photodynamic therapy with sunitinib represents a minimally invasive therapeutic procedure with cancer selectivity for renal cell carcinoma.

Predictors of therapeutic efficacy of 5-aminolevulinic acid-based photodynamic therapy in human prostate cancer.

BACKGROUND: Photodynamic therapy (PDT) is a minimally invasive cancer therapy. However, its therapeutic efficacy for prostate cancer is not yet fully understood. In this study, the predictors of therapeutic efficacy of 5-aminolevulinic acid-based PDT (ALA-PDT) on prostate cancer cells are investigated. MATERIALS AND METHODS: The human prostate cancer cell lines, PC-3, 22Rv1, DU145, and LNCap were used to investigate the effects of ALA-PDT on protoporphyrin IX (PpIX) intracellular accumulation, which was measured by flow cytometry. The cytotoxicity of ALA-PDT was evaluated by MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) assay. The levels of porphyrin metabolism-related enzyme and transporter mRNA were comprehensively evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). Protein expression was evaluated by Western blot. A xenograft model was created using PC-3 and 22Rv1, and then, pathological analysis was performed to determine the therapeutic effect of ALA-PDT RESULTS: PC-3 and LNCap cells showed high accumulation of PpIX and high sensitivity to ALA-PDT, while 22Rv1 and DU145 showed low accumulation of PpIX and low sensitivity to ALA-PDT. ALA-PDT-induced cytotoxicity correlated negatively with PpIX accumulation. The in vitro assays identified the ATP-binding cassette transporter subfamily G2 (ABCG2) transporter dimer as a predictor of treatment response. In vivo immunohistochemical staining of ABCG2 transporter showed low expression in PC-3 cells and high expression in 22Rv1 cells, and ALA-PDT-induced tumor tissue degeneration was greater in PC-3 cells than in 22Rv1 cells. CONCLUSION: The ABCG2 transporter is a useful predictor of the therapeutic effect of ALA-PDT on human prostate cancer cells.

Real-world experience with 5-aminolevulinic acid for the photodynamic diagnosis of bladder cancer: Diagnostic accuracy and safety.

BACKGROUND: 5-Aminolevulinic acid (ALA)-mediated photodynamic diagnosis (PDD) has recently been approved in Japan for the management of non-muscle invasive bladder cancer. As such, the current study aimed to investigate the real-world diagnostic accuracy and safety of ALA-PDD-assisted transurethral resection of bladder tumor (TURBT). METHODS: A total of 76 patients who underwent PDD-assisted TURBT were enrolled. ALA (20 mg/kg body weight) was orally administered before TURBT. Fluorescence observation and tissue collection were performed during surgery, after which diagnostic accuracy was determined. Potential side effects of ALA, including vomiting, hypotension, and liver toxicity, were carefully monitored. RESULTS: The sensitivity, specificity, positive predictive value, and negative predictive value for detecting urothelial carcinoma were 90.1 %, 61.2 %, 55.1 %, and 92.2 % for fluorescence light (FL) and 65.4 %, 88.9 %, 75.7 %, and 83.9 %, for white light (WL) respectively. The mean number of tumors detected per patient was 1.92 and 1.39 for FL and WL (p < 0.05), respectively. No significant differences in the FL sensitivity and specificity were observe among the three patient groups classified according to ALA exposure time after oral administration (2-3, 3-4, and >4 h). ALA-related adverse effects included vomiting (seven cases), hypotension (seven cases, two of which were severe), and liver toxicity (four cases). All side effects disappeared shortly after standard treatment. CONCLUSION: ALA-PDD showed sufficient diagnostic accuracy even after more than 4 h of ALA exposure prior to surgery, as well as acceptable safety profiles.

Mitomycin C-induced cell cycle arrest enhances 5-aminolevulinic acid-based photodynamic therapy for bladder cancer.

BACKGROUND: Photodynamic therapy (PDT) and diagnosis (PDD) using 5-aminolevulinic acid (ALA) to control the production of the intracellular photosensitizer protoporphyrin IX (PpIX) are commonly used clinically. Previously, we demonstrated that dormant and drug-induced dormancy-like cancer cells accumulated high PpIX levels, making them sensitive to ALA-PDT. Because EAU Guidelines awarded a level of evidence of 1a to mitomycin C, the drug is widely used to treat bladder cancer. In this study, we investigated that the effect of mitomycin C-induced cell cycle arrest on porphyrin metabolism, including that induced by ALA-PDT. METHODS: T24 human urinary bladder carcinoma cells were selected for this research. T24 cells were irradiated using a light-emitting diode emitting red light for the ALA-PDT assay. Cell cycle analysis was conducted by flow cytometry using bromodeoxyuridine. Cell viability was confirmed using the MTT or colony formation assay. Furthermore, mRNA gene expression analysis was performed using our previously reported methods. RESULTS: The cell cycle of T24 cells was arrested at G2/M phase by mitomycin C. PpIX accumulation was dramatically increased by mitomycin C treatment. Cell viability after ALA-PDT was remarkably decreased by mitomycin C pretreatment. The gene expression of porphyrin transporters was consistent with the metabolic and morphological results. Finally, we confirmed that ALA-PDT combined with mitomycin C treatment exerted a long-term inhibitory effect on cell proliferation. CONCLUSION: This study demonstrated a new approach to enhance the effects of ALA-PDT using drugs that induce a dormancy-like status and upregulate porphyrin metabolism.