Drug Repurposing of Pantoprazole and Vitamin C Targeting Tumor Microenvironment Conditions Improves Anticancer Effect in Metastatic Castration-Resistant Prostate Cancer.

The effective and economical therapeutic strategy for metastatic castration-resistant prostate cancer (mCRPC) is still requested from patients, who are not available for Lu-177 or Ra-223 treatment. Drug repurposing as a cost-effective and time-saving alternative to traditional drug development has been increasingly discussed. Proton pump inhibitors (PPIs) such as pantroprazole, which are commonly used as antacids, have also been shown to be effective in cancer chemoprevention via induction of apoptosis in multiple cancer cell lines. Vitamin C is an essential micronutrient for human body, has been proposed as a potential anti-cancer agent. In this context, have we investigated the combination of vitamin C and pantoprazole for the management of metastatic castration-resistant prostate cancer (mCRPC). Six chosen human adenocarcinoma cell lines were used to investigate the influence of pantoprazole on the microenvironment of cancer cells (extracellular pH and production of exosomes). Tumor growth and tumor 18F-FDG uptake in PC3 xenografts were analyzed following varied treatment. Our in vitro Results have suggested that pantoprazole enhanced the cytotoxic activity of vitamin C by regulating pH values and production of exosomes in cancer cells. Moreover, the synergistic effect of pantoprazole and vitamin C was pH-dependent since pantoprazole was more effective at a slightly acidic pH. In vivo, the combined treatment using pantoprazole and vitamin C produced better therapeutic outcomes than treatment with vitamin C or pantoprazole alone, as demonstrated via tumor growth and uptake of 18F-FDG. Therefore, we suggest that pantoprazole combined with vitamin C could be as a possible strategy to manage mCRPC.

Increased Tumoral Microenvironmental pH Improves Cytotoxic Effect of Pharmacologic Ascorbic Acid in Castration-Resistant Prostate Cancer Cells.

BACKGROUND: The anticancer potential of pharmacologic ascorbic acid (AA) has been detected in a number of cancer cells. However, in vivo study suggested a strongly reduced cytotoxic activity of AA. It was known that pH could be a critical influencing factor for multiple anticancer treatments. In this study, we explored the influence of pH on the cytotoxicity of ascorbic acid. We employed castration-resistant prostate cancer (CRPC) cell lines PC3 and DU145 to observe the therapeutic effect of AA on PCa cells that were cultured with different pH in vitro. We also analyzed the influence of pH and extracellular oxidation on cytotoxicity of AA in cancer cells using reactive oxygen species (ROS) assay, cellular uptake of AA, and NADPH assay. Male BALB/c nude mice bearing prostate carcinoma xenografts (PC3 or DU145) were used to assess treatment response to AA with or without bicarbonate in vivo. The cellular uptake of AA in PCa xenografts was detected using positron emission tomography (PET). Small animal PET/CT scans were performed on mice after the administration of 6-deoxy-6-[18F] fluoro-L-ascorbic acid (18F-DFA). RESULTS: Our in vitro studies demonstrate that acidic pH attenuates the cytotoxic activity of pharmacologic ascorbic acid by inhibiting AA uptake in PCa cells. Additionally, we found that the cancer cell-selective toxicity of AA depends on ROS. In vivo, combination of AA and bicarbonate could provide a significant better therapeutic outcome in comparison with controls or AA single treated mice. 18F-DFA PET imaging illustrated that the treatment with NaHCO3 could significantly increase the AA uptake in tumor. CONCLUSIONS: The alkalinity of tumor microenvironment plays an important role in anticancer efficiency of AA in CRPC. 18F-DFA PET/CT imaging could predict the therapeutic response of PCa animal model through illustration of tumoral uptake of AA. 18F-DFA might be a potential PET tracer in clinical diagnosis and treatment for CRPC.

Human Biodistribution and Radiation Dosimetry of S-11C-Methyl-L-Cysteine Using Whole-Body PET.

PURPOSE: S-C-Methyl-L-cysteine (C-MCYS) is a recently developed amino acid PET tracer for tumor imaging. The present study estimated human radiation absorbed dose of C-MCYS in healthy volunteers based on whole-body PET imaging. METHODS: Five sequential whole-body PET scans were performed on 6 healthy volunteers after injection of C-MCYS. Each scan contained of approximately 7 to 10 bed positions, and total scan time of each volunteer was approximately 70 to 85 minutes. Regions of interest were drawn on PET images of source organs. Residence times of 13 source organs for men and 14 source organs for women were calculated from the organ-specific time-activity curves. Absorbed dose estimates were performed from organ residence time by using the medical internal radiation dosimetry method. RESULTS: All volunteers showed initial high uptake in liver, heart, kidneys, pancreas, spleen, and uterus (only women), and followed by rapid clearance. There was very little activity residual in most of the organs except for the liver at the last emission scan time (approximately 75 minutes). The liver was the dose-limiting critical organ with the highest radiation-absorbed dose (1.01E-02 ± 2.64E-03 mGy/MBq), followed by the heart (9.09E-03 ± 1.40E-03 mGy/MBq), and the kidneys (7.12E-03 ± 9.44E-04 mGy/MBq). The effective dose to the whole body was 4.03E-03 ± 1.65E-04 mSv/MBq. A routine injection of 555 MBq (15 mCi) of C-MCYS would lead to an estimated effective dose of 2.24 ± 0.092 mSv. CONCLUSIONS: The potential radiation risks associated with C-MCYS PET imaging are within accepted limits. C-MCYS is a safe amino acid PET tracer for tumor imaging and can be used in further clinical studies.

Radiofrequency ablation before intratumoral injection of (131)I-chTNT improves the tumor-to-normal tissue ratio in solid VX2 tumor.

PURPOSE: This study was aimed to investigate whether the tumor necrosis induced by radiofrequency ablation (RFA) can improve the ratio of tumor-to-normal tissue (T/NT) after intratumoral injection of (131)I-chTNT. MATERIALS AND METHOD: Eighteen New Zealand rabbits bearing VX2 tumor on the thigh were randomly divided into two treatment groups (control group: intratumoral injection of (131)I-chTNT alone; RFA group: RFA + intratumoral injection of (131)I-chTNT 3 days after RFA) and each group was further divided into three subgroups I, II, and III (1-2 cm, 2-3 cm, and 3-4 cm in maximum diameter, respectively), by the tumor size. SPECT was performed to evaluate the T/NT on days 1, 8, and 15 after (131)I-chTNT injection. RESULTS: After treatment, all rabbits underwent the SPECT whole-body scan and the T/NT was analyzed. The results showed that T/NT in the RFA group (55.45±41.83) was significantly higher compared with the control group (7.23±5.61) (F=18.89, p=0.001). Meanwhile, a linear ascending trend was found for T/NT in the RFA group along with the follow-up time (r=0.47, p=0.01). The tumor size or the dose of (131)I-TNT injection had no significant effect on the variation of T/NT in both groups (p>0.05). CONCLUSION: RFA before intratumoral injection of (131)I-chTNT can dramatically improve T/NT, demonstrating the potential application of this combination therapy.

Influence of hippophae rhamnoides on two appetite factors, gastric emptying and metabolic parameters, in children with functional dyspepsia.

Our aim was to explore in children with functional dyspepsia the effect of hippophae rhamnoides on the levels of plasma appetite factors and on their gastrointestinal motility. A hundred and twenty children with functional dyspepsia were randomly divided into three groups: Group I (treated with hippophae rhamnoides), Group II (treated with domperidone), and Group III (treated with hippophae rhamnoides plus domperidone). The treatment lasted for eight weeks. The levels of plasma leptin (LP) and neuropeptide Y (NPY) were measured before and after treatment. All patients underwent a gastric emptying (GE) test by ultrasound (US) to measure the rate of postprandial gastric antrum residual, at 30min, 60min, 90min and 120min. The average value of subcutaneous fat, body fat percentage, upper arm girth and body mass index (BMI) were also measured. To compare the US with the radionuclide GE test 14 healthy adults volunteers were tested by both GE techniques. We found that the levels of LP and NPY in plasma were markedly higher after treatment in Groups I and III than in Group II. The postprandial gastric antrum remains at 60min, 90min and 120min in Groups I and III fell greatly and the thickness of skin fold (SF), body fat percentage and arm girth increased (P<0.05). The GE half emptying time of a mixed liquid-solid food measured by B US and by the radionuclide technique in the same individuals was similar (P>0.05). In conclusion, in children's functional dyspepsia, our study showed that hippophae rhamnoides increases the levels of appetite factors, leptin and neuropeptide Y, increases gastric emptying and gastrointestinal digestive function, children's growth and development.

The clinical value of Tc-99m TRODAT-1 SPECT for evaluating disease severity in young patients with symptomatic and asymptomatic Wilson disease.

PURPOSE: The purpose of this study was to determine the clinical value of applying Tc-99m TRODAT-1 single photon emission computed tomography (SPECT) of the dopamine transporter to evaluate disease severity in young patients with symptomatic or asymptomatic Wilson disease (WD). MATERIALS AND METHODS: The evaluation of Tc-99m TRODAT-1 SPECT was performed in 18 patients with symptomatic WD, 13 patients with asymptomatic WD, and, as controls, 12 normal volunteers matched for age and gender. The neurologic symptoms of symptomatic patients were evaluated by an experienced neurologist. The ratios of specific striatal Tc-99m TRODAT-1 binding [with the cerebellum (CB) as the reference region] were calculated as striatum (ST)/CB and compared among the 3 groups. Using correlation analysis, the ratios for the WD patients were compared with clinical data on the severity of neurologic symptoms. RESULTS: Significant differences of ST/CB ratios were found among the 3 groups (Sym vs. Nor, P = 0.000; Asym vs. Nor, P = 0.036; Sym vs. Asym, P = 0.011, respectively). In 23 patients (18 with symptomatic WD, 5 with asymptomatic WD), the posterior putamina showed more remarkable deformation and decreased radiotracer uptake. The ST/CB ratios correlated negatively with the severity of neurologic symptoms (r = -0.80, P < 0.01). CONCLUSIONS: The decreased striatal Tc-99m TRODAT-1 uptake found in young WD patients, including symptomatic WD and some asymptomatic WD, as detected with SPECT, seems to indicate presynaptic damage of the dopaminergic nerve terminals. The decrease in radiotracer uptake was more prominent in the posterior putamina than in the caudate heads. The Tc-99m TRODAT-1 SPECT method can be used effectively for evaluating disease severity in WD.

Comparison of three- and two-dimensional sonography in diagnosis of gallbladder diseases: preliminary experience.

OBJECTIVE: To compare three-dimensional sonography with two-dimensional sonography for diagnosis of gallbladder diseases. METHODS: Sixty-three patients with gallbladder diseases were examined with two- and three-dimensional sonography. The morphologic features presented on both modalities were analyzed, and the diagnostic accuracies of both modalities were evaluated and compared. RESULTS: Both two- and three-dimensional sonography facilitated correct diagnosis in all patients with gallstones. Three-dimensional sonography had no influence on the diagnosis of gallstones compared with two-dimensional sonography. Three-dimensional sonography showed the granular surfaces in 18 (81.8%) of 22 cases of polypoid lesions and the pedunculated fundus in 19 (86.4%) of 22, whereas two-dimensional sonography displayed them in 10 (45.5%) and 3 (13.6%) of 22, respectively (P < .05 and .001). Three- and two-dimensional sonography made correct differential diagnoses between non-neoplastic and neoplastic polyps in 20 (90.9%) and 12 (54.5%) of 22, respectively (P < .05). In gallbladder carcinoma, both three- and two-dimensional sonography accurately showed all the associated gallstones and intrahepatic bile duct dilatation. Two-dimensional sonography could not correctly define the locations of the lesions in 2 (28.6%) and tumor extension in 1 (14.3%) of 7 cases with pathologically proved gallbladder cancer, whereas three-dimensional sonography improved the diagnosis in these cases. CONCLUSIONS: Three-dimensional sonography adds no advantages for diagnosis of gallstones compared with two-dimensional sonography, but it is better than two-dimensional sonography for differential diagnosis of gallbladder polyps and may improve the localization and staging for gallbladder carcinoma; however, additional studies are needed for further determination.