LET Dependence of 8-Hydroxy-2'-deoxyguanosine (8-OHdG) Generation in Mammalian Cells under Air-Saturated and Hypoxic Conditions: A Possible Experimental Approach to the Mechanism of the Decreasing Oxygen Effect in the High-LET Region.

One of the most distinguished features in biological effects of heavy ions would be the decrease of oxygen effect in the high-LET region. This feature has been referred to as the radiobiological basis for the control of hypoxic fraction in cancer radiotherapy. However, mechanisms to explain this phenomenon have not been fully understood. One of the explanations was given by the oxygen in the track hypothesis, which proposes that oxygen is produced along ion tracks even in the hypoxic irradiation condition. In the present study, we designed an experimental approach to support this hypothesis by using 8-hydroxy-2'-deoxyguanosine (8-OHdG) as DNA damage requiring oxygen to produce. The LET dependence of 8-OHdG under hypoxic condition revealed that with increasing LET 8-OHdG yield seems to increase, despite that the yield of OH radical, which is also required for the production of 8-OHdG, decreases in the high-LET region. This result is consistent with the explanation that the local generation of oxygen along ion tracks contributes to the increase of 8-OHdG yield.

DOSE-RATE AND CELL-KILLING SENSITIVITY OF HIGH-LINEAR ENERGY TRANSFER ION BEAM.

It is believed that the dose-rate of radiation will have an influence on cell sensitivity. The dose-rate effects on cell survival can be expressed by the change of the ß term in the linear quadratic model. The value at a high-dose-rate decreases below 60 Gy/h and reaches zero at 0.2 Gy/h or less for photons. However, the effect for a high-LET ion-beam is not well known. At HIMAC, cells were exposed to 70 keV/µm carbon-ion beams at different dose-rates between 0.5 and 600 Gy/h at room temperature. The ß values for all survival curves show no significant differences among the dose-rates tested for HSG, V79 and CHO cells. Changing the ion-beam dose-rate had no effect on cell survival. This suggests that high-LET particle beams, such as galactic cosmic rays, may not exhibit a dose-rate effect on cell survival. Low-dose-rate radiation showed an effect similar to high-dose-rate radiation.

Adaptation of the microdosimetric kinetic model to hypoxia.

Ion beams present a potential advantage in terms of treatment of lesions with hypoxic regions. In order to use this potential, it is important to accurately model the cell survival of oxic as well as hypoxic cells. In this work, an adaptation of the microdosimetric kinetic (MK) model making it possible to account for cell hypoxia is presented. The adaptation relies on the modification of damage quantity (double strand breaks and more complex lesions) due to the radiation. Model parameters such as domain size and nucleus size are then adapted through a fitting procedure. We applied this approach to two cell lines, HSG and V79 for helium, carbon and neon ions. A similar behaviour of the parameters was found for the two cell lines, namely a reduction of the domain size and an increase in the sensitive nuclear volume of hypoxic cells compared to those of oxic cells. In terms of oxygen enhancement ratio (OER), the experimental data behaviour can be reproduced, including dependence on particle type at the same linear energy transfer (LET). Errors on the cell survival prediction are of the same order of magnitude than for the original MK model. Our adaptation makes it possible to account for hypoxia without modelling the OER as a function of the LET of the particles, but directly accounting for hypoxic cell survival data.

Radiosensitivity of pimonidazole-unlabelled intratumour quiescent cell population to γ-rays, accelerated carbon ion beams and boron neutron capture reaction.

OBJECTIVES: To detect the radiosensitivity of intratumour quiescent (Q) cells unlabelled with pimonidazole to accelerated carbon ion beams and the boron neutron capture reaction (BNCR). METHODS: EL4 tumour-bearing C57BL/J mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumour proliferating (P) cells. After the administration of pimonidazole, tumours were irradiated with γ-rays, accelerated carbon ion beams or reactor neutron beams with the prior administration of a (10)B-carrier. Responses of intratumour Q and total (P+Q) cell populations were assessed based on frequencies of micronucleation and apoptosis using immunofluorescence staining for BrdU. The response of pimonidazole-unlabelled tumour cells was assessed by means of apoptosis frequency using immunofluorescence staining for pimonidazole. RESULTS: Following γ-ray irradiation, the pimonidazole-unlabelled tumour cell fraction showed significantly enhanced radiosensitivity compared with the whole tumour cell fraction, more remarkably in the Q than total cell populations. However, a significantly greater decrease in radiosensitivity in the pimonidazole-unlabelled cell fraction, evaluated using a delayed assay or a decrease in radiation dose rate, was more clearly observed among the Q than total cells. These changes in radiosensitivity were suppressed following carbon ion beam and neutron beam-only irradiaton. In the BNCR, the use of a (10)B-carrier, especially L-para-boronophenylalanine-(10)B, enhanced the sensitivity of the pimonidazole-unlabelled cells more clearly in the Q than total cells. CONCLUSION: The radiosensitivity of the pimonidazole-unlabelled cell fraction depends on the quality of radiation delivered and characteristics of the (10)B-carrier used in the BNCR. ADVANCES IN KNOWLEDGE: The pimonidazole-unlabelled subfraction of Q tumour cells may be a critical target in tumour control.

Induction of DNA DSB and its rejoining in clamped and non-clamped tumours after exposure to carbon ion beams in comparison to X rays.

We studied double-strand breaks (DSB) induction and rejoining in clamped and non-clamped transplanted tumours in mice leg after exposure to 80 keV µm(-1) carbon ions and X rays. The yields of DSB in the tumours were analysed by a static-field gel electrophoresis. The OER of DSB after X rays was 1.68±0.31, and this value was not changed after 1 h rejoining time (1.40±0.26). These damages in oxygenated conditions were rejoined 60-70% within 1 h in situ. No difference was found between the exposure to X rays and carbon ions for the induction and rejoining of DSB. Thus, the values of OER and rejoined fraction after exposure to carbon ions were similar to those after X rays, and the calculated relative biological effectivenesses of carbon ion were around 1 under both oxygen conditions. The yields of DSB in vivo depend on exposure doses, oxygen conditions and rejoining time, but not on the types of radiation quality.

Significance of manipulating tumour hypoxia and radiation dose rate in terms of local tumour response and lung metastatic potential, referring to the response of quiescent cell populations.

The purpose of this study was to evaluate the influence of manipulating intratumour oxygenation status and radiation dose rate on local tumour response and lung metastases following radiotherapy, referring to the response of quiescent cell populations within irradiated tumours. B16-BL6 melanoma tumour-bearing C57BL/6 mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. They received gamma-ray irradiation at high dose rate (HDR) or reduced dose rate (RDR) following treatment with the acute hypoxia-releasing agent nicotinamide or local hyperthermia at mild temperatures (MTH). Immediately after the irradiation, cells from some tumours were isolated and incubated with a cytokinesis blocker. The responses of the quiescent (Q) and total (proliferating + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumour-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated. Following HDR irradiation, nicotinamide and MTH enhanced the sensitivity of the total and Q-cell populations, respectively. The decrease in sensitivity at RDR irradiation compared with HDR irradiation was slightly inhibited by MTH, especially in Q cells. Without gamma-ray irradiation, nicotinamide treatment tended to reduce the number of lung metastases. With gamma-rays, in combination with nicotinamide or MTH, especially the former, HDR irradiation decreased the number of metastases more remarkably than RDR irradiation. Manipulating both tumour hypoxia and irradiation dose rate have the potential to influence lung metastasis. The combination with the acute hypoxia-releasing agent nicotinamide may be more promising in HDR than RDR irradiation in terms of reducing the number of lung metastases.

[Case with cardiac myxoma causing cerebral metastasis after cardiac tumor resection].

We report a case of cardiac myxoma causing cerebral metastasis after cardiac tumor resection. A 68-year-old man with a cerebral infarction was admitted to our hospital. A cardioembolic source was suspected and echocardiography was performed. In that examination, a cardiac tumor was found in the left atrium. Tumor resection was performed urgently and his postoperative course was uneventful. After the operation he had no new episodes of cerebral deficit. However 6 months after the operation, he complained of headaches. The brain computed tomography (CT) showed there were multiple high-density areas. One of the tumors was resected and the tumor was diagnosed pathologically as metastasis of cardiac myxoma. Brain metastases were treated with 40.8 Gy whole-brain radiation therapy. As the result the tumors were effectively treated and reduced.

Threshold photoelectron spectroscopy on inner-valence ionic states of NO.

The NO(+) states lying in the ionization region of 20-40 eV have been investigated by high-resolution threshold photoelectron spectroscopy and a configuration interaction calculation. Substantial agreement between the structures on the present experimental and theoretical spectra in the 21-27 eV range enables us to assign the relevant inner-valence ionic states unambiguously. The dissociation products from the ion states are measured with threshold photoelectron-photoion coincidence spectroscopy, and the dissociation processes are discussed with reference to the potential energy curves calculated. Sharp peaks are observed in the ionization region of 27.5-35 eV, which are allocated to ionic Rydberg states converging to NO(2+).

Thymidylate synthase predictive power is overcome by irinotecan combination therapy with S-1 for gastric cancer.

The predictive values of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) gene expressions were retrospectively evaluated in patients with gastric cancer treated by a regimen containing S-1. The study population consisted of 53 patients registered into different two phase II studies for metastatic gastric cancer; 27 patients treated by S-1-alone study: 26 patients treated with S-1 combined with irinotecan (CPT-11). TS and DPD gene expressions in primary tumours were measured by the real-time reverse transcription PCR method. There was no statistical difference in DPD gene expression in terms of response in cases treated with S-1 alone and those treated with S-1 plus CPT-11. TS mRNA of responding tumours was lower than that of nonresponding ones when treated with S-1 (P<0.005). In the S-1-alone group, taking TS cutoff as the median values, the response rate in the low TS group was 50%, but only 8% in the high TS group (P<0.05). Patients with low TS gene expression survived longer than those with high TS gene expression (P<0.0001). However, there was no statistically significant difference in response rate and survival between patients with low TS tumours and those with high TS tumours, when the cutoff was taken as the median value of TS gene expression in the group treated with S-1 plus CPT-11. In conclusion, treatment effects of S-1 monotherapy for gastric cancer were determined by the status of TS gene expression, regardless of DPD gene expression. TS predictive power was overcome by CPT-11 combination therapy with S-1.

Both gene expression for orotate phosphoribosyltransferase and its ratio to dihydropyrimidine dehydrogenase influence outcome following fluoropyrimidine-based chemotherapy for metastatic colorectal cancer.

Activation of 5-fluorouracil into its nucleotides requires phosphorylation by three pathways involving orotate phosphoribosyl-transferase (OPRT), uridine phosphorylase (UP), or thymidine phosphorylase (TP). In this study, we investigated the association between gene expressions of these three enzymes and antitumour effect. Gene expressions in primary colorectal tumours were analysed by a real-time reverse transcriptional-polymerase chain reaction method in 37 patients receiving oral treatment of tegafur-uracil and leucovorin for metastatic diseases. The median values of OPRT mRNA expressions were 1.39 and 0.85 for responding tumours and nonresponding tumours, respectively, showing a statistically significant difference (P=0.0008). Responding tumours had statistically lower expressions of TP mRNA than nonresponding tumours (P=0.006). However, there was no difference in UP mRNA expression between responding and nonresponding tumours. Patients with high OPRT (>/=1.0) gene expression survived longer than those with low OPRT (<1.0) expression. Dihydropyrimidine dehydrogenase (DPD) gene expressions were measured. Responding tumours had a statistically higher OPRT/DPD ratio than the nonresponding ones (P=0.003). When the median value of the OPRT/DPD ratio was selected as the cutoff value, patients with a high OPRT/DPD ratio survived statistically longer than those with a low ratio (P=0.0014). In conclusion, both the expression of OPRT gene and the OPRT/DPD ratio might be useful as predictive parameters for the efficacy of fluoropyrimidine-based chemotherapy for metastatic colorectal cancer.

Angiosarcoma of the breast: report of a case and its findings of MRI.

A 67-year-old woman with angiosarcoma of the left breast is presented. Physical findings showed a hard mass in the left breast with skin discoloration and erythema. Mammography showed a high density shadow in the mass without microcalcification and spicula. On ultrasonography, a hypoechoic mass with an ill-defined boundary was detected. On MRI, the tumor had low signal intensity on T1-weighted images, and higher signal intensity on T2-weighted images. MRI with Gd-DTPA images showed higher signal intensity on T1-weighted images with relatively lower intensity in the central area of the tumor. The artery supplying the tumor derived from the left inner thoracic artery and was visualized on three-dimensional dynamic MRI angiography. Initially misdiagnosed as inflammatory breast cancer, an arterial injection of CPA (100 mg) and 5-FU (500 mg) had been performed preoperatively. The definitive diagnosis of angiosarcoma was established by intraoperative frozen section examination. She underwent modified radical mastectomy and is now free of recurrence. This case emphasizes the difficulties in the clinical diagnosis of angiosarcoma of the breast.

Thymidylate synthase gene expression in primary colorectal cancer and metastatic sites.

Thymidylate synthase (TS) expression has been identified as an important predictor of response to 5-fluorouracil (5-FU). However, there is relatively little information on the heterogeneity of TS mRNA expression between primary and metastatic tumors, as well as differential expression of TS mRNA in metastatic sites. In this study, TS mRNA expression was measured in primary colorectal cancer tumors and various metastatic tumors. The median TS/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA ratio was 0.98 in primary tumors, 0.70 in liver metastases, 1.92 in lymph node metastases, and 3.42 in pulmonary metastases. A significantly higher expression of TS mRNA was observed in pulmonary and lymph node metastases compared with their respective primary tumors. In contrast, TS mRNA expression in hepatic metastases was significantly lower than in primary tumors. Similar results were observed in tumors obtained from the same patient. These results may explain the difference in the clinical response to 5-FU-based chemotherapy between various metastatic sites. The discordant TS expression between primary and metastatic tumors is a critical factor that must be taken into account when TS is being used as a predictive biomarker for the antitumor effect of 5-FU-based chemotherapy.

Telomere shortening in gastric carcinoma with aging despite telomerase activation.

In the present study, we analyzed both telomere length and telomerase activity in surgical and autopsy samples of non-neoplastic mucosa and carcinomas of the stomach. Telomere length, determined by Southern blot analysis, demonstrated progressive shortening with age in non-neoplastic gastric mucosal specimens from 38 human subjects aged between 0 and 99 years, with an average annual loss rate of 46 base pairs (bp). The mean (+/- SD) telomere length in 21 gastric carcinomas was 7.0 +/- 1.6 x 10(3) base pairs (1.6 kbp). In 20 (95%) of the 21 subjects, the values were smaller than those in the nonneoplastic gastric mucosa (mean shortening 1.8 kbp), although a strong correlation was observed for the paired data (r = 0.69, P = 0.0004). Similarly, telomere lengths in carcinomas were shorter than those for intestinal metaplasia (a mean difference of 1.1 kbp). Telomerase activity, estimated using the telomeric repeat amplification protocol assay, was positive in 18 (86%) of the 21 gastric carcinomas, without significant differences among the three histological types (well, moderately, and poorly differentiated adenocarcinomas) or with sex or age. The results suggest that telomere length and possibly shortening rates vary with the individual, and that examination of both non-neoplastic mucosa and tumors is necessary to improve our understanding of the significance of telomerase in neoplasia.

The novel hypoglycemic agent YM440 normalizes hyperglycemia without changing body fat weight in diabetic db/db mice.

To determine the relationship between hypoglycemic activity and body weight gain induced by insulin sensitizers, we compared the effects of thiazolidinedione analogs (troglitazone and pioglitazone) and the oxadiazolidinedione analog (Z)-1,4-bis4[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phen oxy¿but-2-ene (YM440) in diabetic db/db mice. Oral treatment with YM440(100 mg/kg) for 28 days decreased the blood glucose concentration (control v YM440, 418 +/- 12 v243 +/- 44 mg/dL). The hypoglycemic activity of this agent was comparable to that of troglitazone (300 mg/kg) and pioglitazone (100 mg/kg). There were no changes in food intake among the groups. Troglitazone and pioglitazone, but not YM440, significantly increased body weight gain during treatment (control, 7.2 +/- 0.5 g; YM440, 7.5 +/- 0.8 g; troglitazone, 10.9 +/- 0.8 g; and pioglitazone, 14.5 +/- 1.1 g). To further assess whether the increase in body weight by troglitazone or pioglitazone was due to adipogenesis, the weight of intraabdominal fat tissue (epididymal, retroperitoneal, and perirenal) was determined. There were no differences in the total weight of visceral fat between the control and YM440 treatment (3.53 +/- 0.23 and 3.60 +/- 0.16 g). In contrast, troglitazone and pioglitazone significantly increased the fat weight (4.31 +/- 0.13 and 4.66 +/- 0.19 g). Thiazolidinediones are known as ligands for peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear receptor responsible for adipogenesis. Troglitazone and pioglitazone activated PPARgamma and increased triglyceride accumulation and mRNA expression of fatty acid-binding protein (FABP) in 3T3-L1 cells. However, YM440 had no effect on these indices for adipocyte differentiation. These results suggest that the mechanism is different for the hypoglycemic action of YM440 versus the thiazolidinediones. YM440 ameliorates hyperglycemia without changing PPARgamma activity, adipocyte differentiation, or fat weight. Thus, YM440 could be a useful hypoglycemic agent for the treatment of non-insulin-dependent diabetes mellitus (NIDDM) without affecting body weight.

Structure-activity relationship of hydroxamate-based inhibitors on membrane-bound Fas ligand and TNF-alpha processing.

Both Fas ligand (FasL) and tumor necrosis factor-alpha (TNF-alpha) are type II integral membrane proteins. Recently, we have reported that FasL is processed to a soluble form by an unknown metalloproteinase at the cell surface and some hydroxamate matrix metalloproteinase (MMP) inhibitors inhibit the processing similar to the case observed with TNF-1alpha. We studied the inhibitory effects of various hydroxamate MMP inhibitors on FasL and TNF-alpha processing in order to characterize the processing enzymes using human FasL cDNA transfectants and LPS-stimulated THP-1 cells. It turned out that (1) the P1' group of hydroxamates was very important for the selective inhibitory activity toward TNF-alpha and FasL processing, (2) P1' 3-phenylpropyl group was favorable for the inhibition of FasL processing, and (3) P1' isobutyl and isopropyl groups were favorable for that of TNF-alpha processing. These differences in sensitivity to inhibitors imply that (1) membrane-bound FasL and TNF-alpha might be processed by distinct metalloproteinases, (2) the S1' site of FasL processing enzyme differs from that of MMP-1 and MMP-9, but appears to be similar to that of MMP-3, and (3) the S1' site of TNF-alpha processing enzyme is smaller than that of FasL processing enzyme. These results would be helpful in designing a more selective inhibitor.

Estimation of glycogen levels in human colorectal cancer tissue: relationship with cell cycle and tumor outgrowth.

In this study, we quantitatively measured glycogen levels in tissue samples obtained from tumors, regions adjacent to tumor, and regions of normal colorectum to determine whether the levels were related to cell cycle and cancer growth. Glycogen levels were analyzed in relation to histopathological factors, (tumor size and stage of disease) and cell cycle progression. The glycogen level was found to be highest in the cancer tissue, lower in normal tissue, and lowest in the adjacent tissue. The difference in glycogen level between the cancer tissue and the other two regions was significant (P < 0.05). There was a negative correlation between glycogen level and tumor size, but it was not significant. The level of glycogen in cancer tissues decreased as the stage of the disease progressed, but a significant difference was not found between stages. There was a negative correlation between the glycogen level and the proliferation index. There was a positive correlation between the glycogen level and the proportion of cancer cells in G1 phase, while there was a negative correlation with S and G2M phases. Glycogen levels were highest in cancers with a high proportion of cells in G1, and decreased with progression to S phase. It may be that glycogen is utilized in the progression to S phase, and the cancer tissues are supplied with glycogen from the tumors themselves as well as their adjacent tissues. Cancer growth may be inhibited by artificial control of the glycogen level in the G1 phase of cancer cells.

A new instrument for hemostatic vascular management in endoscopic surgery: diode laser (STATLase-SDL) and its handpiece (dual hook).

OBJECTIVE: The authors described experimental data in hemostatic vascular transection using a STATLase-SDL with a 780-865 nm GaA/As diode wavelength and its handpiece, Dual Hook (DH). SUMMARY BACKGROUND DATA: The STATLase-SDL and DH are newly developed devices for endoscopic surgery. It seems that the device has improved hemostatic cutting ability. METHODS: The DH was applied to the abdominal aorta (< 2 mm) of Japanese white rabbits (n = 15) under general anesthesia. Tissue temperature during laser transection and interluminal bursting pressures were measured. Histopathological examinations at the cut end were carried out by hematoxylin-eosin (H&E) and elastica Van Gleson's (EVG) stainings. To investigate short-term effects 11 days postoperatively, the cut ends of the vessels were examined histologically in the heminephrectomy group. RESULTS: The DH hemostatistically cut through arteries up to 2 mm in diameter. Temperatures at the inner hook and in adjunct tissue were higher than 160 degrees C, while that at the outer hook was lower than 80 degrees C. The bursting pressures immediately after transection was 307.2 +/- 35.2 mm Hg at a laser power of 8 W (n = 5), and 295.6 +/- 28.7 mm Hg at 10 W (n = 5). Histological examination of the transected sites on the vessels revealed well-opposed tissue welding of the vascular wall. Absence of fragmentation in the welding of the internal elastic lamina is crucial for closure of the vessel stump. Up to 11 days postoperatively, there were no direct complications related to the use of the DH. CONCLUSIONS: The STATLase-SDL and DH have good hemostatic cutting ability and might be suitable for endoscopic surgery.

Overexpression of nm23-H2/NDP kinase B in a human oral squamous cell carcinoma cell line results in reduced metastasis, differentiated phenotype in the metastatic site, and growth factor-independent proliferative activity in culture.

The metastasis suppressor activity of nm23/nucleoside diphosphate (NDP) kinase was assessed using human oral squamous cell carcinoma (SCC) cell lines. When the expression of nm23/NDP kinase was compared among several SCC cell lines, nm23-H2/NDP kinase B gene product, but not nm23-HI/NDP kinase A gene product, was reduced in the metastatic cells. Transfection of nm23-H2 into the metastatic SCC cell line LMF4 caused reduction in the lung metastasis in an experimental metastasis assay. A histological analysis of the pulmonary metastatic foci revealed that although foci of the control clones were composed of anaplastic squamous cells, those of the nm23-H2-transfected clones consisted of mostly well-differentiated cells mimicking normal stratified epithelial constitution. The transfected cells were morphologically indistinguishable from the control ones in culture, but they differed from each other in that the former cells proliferated faster than the latter, became less serum dependent, and lost responsiveness to growth factors such as platelet-derived growth factor, insulin-like growth factor I, and insulin, although both clones retained sensitivity to transferrin. These results demonstrate that nm23-H2 protein does have metastasis suppressor activity for human SCC cells and suggest that this activity may be elicited by modulating growth and/or differentiation potential in response to environmental factors.

In vivo effects of pioglitazone on uncoupling protein-2 and -3 mRNA levels in skeletal muscle of hyperglycemic KK mice.

Pioglitazone is a thiazolidinedione drug (TZD) which potently and specifically stimulates peroxisome proliferator-activated receptor gamma (PPAR gamma) and sensitizes cells to insulin. Since TZDs are thought to increase energy expenditure, changes in mitochondrial thermogenesis uncoupling protein-2 and -3 mRNA levels in response to pioglitazone treatment were measured in mouse skeletal muscle. Normally hyperglycemic and hyperinsulinemic KK/Ta mice were given pioglitazone for 2 weeks to treat this non-insulin dependent diabetes-like condition. During treatment, UCP2 mRNA levels increased to 185% of normal untreated control levels in soleus muscle. In contrast, UCP3 mRNA levels significantly decreased, up to 67% of normal untreated control levels. Interestingly, UCP3 mRNA levels correlated quite strongly with blood glucose levels, with r = 0.82 for gastrocnemius tissue and r = 0.92 for soleus tissue. These results may indicate that pioglitazone increases glucose catabolism by direct upregulation of muscle UCP2 gene expression in vivo. Therefore, UCP3 gene expression is controlled by a different mechanism than UCP2 expression.

The clinical significance of u-FCC, an antigen of anti-fucosylceramide antibody found in urine, in patients with gastric and colorectal carcinoma.

BACKGROUND: It has already been shown that the production of fucosylceramide, an aberrant glycolipid, is associated with neoplastic changes in human tissues. The authors of this study designed a sandwich radioimmunoassay (RIA) using a mouse monoclonal anti-fucosylceramide antibody, PC47H, designated as PC/PC RIA, and measured the level of u-FCC, an antigen of PC47H, in the urine of cancer patients. METHODS: The cohort comprised 41 patients with gastric carcinoma, 35 with colorectal carcinoma, 34 with other malignancies, 14 with cholelithiasis, 18 with gastric ulcer, and 110 healthy individuals. The u-FCC was quantified by PC/PC RIA. The cutoff value of u-FCC was obtained from the 110 healthy individuals, and the rates of positivity for gastric and colorectal carcinoma patients were evaluated. RESULTS: The rates of u-FCC positivity were 63% for patients with gastric carcinoma and 69% for colorectal carcinoma patients. The rate was only 1% (1/110) for the healthy individuals. The u-FCC value did not correlate with the values of either CA 19-9 or carcinoembryonic antigen (CEA). In a combination assay of u-FCC with CA 19-9 and CEA, the positivity rates were 84% for gastric carcinoma patients and 85% for colorectal carcinoma patients. CONCLUSIONS: Gastric and colorectal carcinoma patients have significantly high levels of u-FCC in their urine compared with normal individuals.