Ubiquitin-specific protease 14 expression in colorectal cancer is associated with liver and lymph node metastases

Ubiquitin-specific protease 14, also known as the 60 kDa subunit of tRNA-guanine transglycosylase (USP14/TGT60 kD), belongs to the ubiquitin-specific processing protease (UBP) family. USP14/TGT60 kD expression in leukemic and colorectal cancer cell lines, and the suppression of such an expression after the induction of cell differentiation have been reported. In the present study, we attempted to clarify whether USP14/TGT60 kD overexpression affects the clinicopathological features of colorectal cancer. Immunohistochemically, USP14/TGT60 kD was absent or weakly localized in the cytoplasm of normal colorectal epithelial cells. In 18 of 99 (18.2%) colorectal cancer patients, USP14/TGT60 kD was strongly detected in the cytoplasm of cancer cells. USP14/TGT60 kD expression correlated with pathological stage (P=0.03), and lymph node (P=0.03) and liver (P=0.03) metastases. Furthermore, the percentage of patients strongly positive for USP14/TGT60 kD expression increased with pathological stage. The overall survival rate was worse in patients with a high USP14/TGT60 kD expression level than in those with a low USP14/TGT60 kD expression level. Our results suggest that USP14/TGT60 kD also controls the fate of proteins that regulate tumor invasion and metastasis.     

PET tracers for imaging of the dopaminergic system

The dopaminergic system plays a major role in neurological and psychiatric disorders such as Parkinson's disease, Huntington's disease, tardive dyskinea and schizophrenia. Knowledge on altered dopamine synthesis, receptor densities and status are important for understanding the mechanisms underlying the pathogenesis and therapy of diseases. PET provides a non-invasive tool to investigate these features in vivo, provided the availability of suitable radiopharmaceuticals. To investigate presynaptic function, PET-tracers have been developed to measure dopamine synthesis and transport. For the former the most commonly used tracers are 6-[(18)F]FDOPA and 6-[(18)F]FMT, whereas for the latter several (11)C/(18)F-labeled tropane analogues are being clinically used. Postsynaptically, dopamine exerts actions through several subtypes of the dopamine receptor. The dopamine receptor family consists of 5 subtypes D(1)-D(5). In order to investigate the role of each receptor subtype, selective and high-affinity PET-radioligands are required. For the dopamine D(1)-subtype the most commonly used ligand is [(11)C]SCH 23390 or [(11)C]NNC 112, whereas for the D(2)/D(3)-subtype [(11)C]raclopride is a common tracer. [(18)F]Fallypride is a suitable PET-tracer for the investigation of extrapyramidal D(2)-receptors. For the other subtypes no suitable radioligands have been developed yet. This paper gives an overview of the current status on dopamine PET-tracers and the development of new lead compounds as potential PET-tracers by medicinal chemistry.     

Sigma receptor ligands: possible application as therapeutic drugs and as radiopharmaceuticals

Sigma receptors are classified into sigma(1) and sigma(2) subtypes. These subtypes display a different tissue distribution and a distinct physiological and pharmacological profile in the central and peripheral nervous system. The characterization of these subtypes and the discovery of new specific sigma receptor ligands demonstrated that sigma receptors are novel targets for the therapeutic treatment of neuropsychiatric diseases (schizophrenia, depression, and cognition), brain ischemia, and cocaine addiction. Furthermore, imaging of sigma(1) receptors in the human brain using specific PET radioligands has started. In addition, the two sigma receptor subtypes are also expressed on tumor cells, where they could be of prognostic relevance. The ability of sigma(2) receptor agonists to inhibit tumor cell proliferation through mechanisms that might involve apoptosis, intracellular Ca(2+), and sphingolipids has promoted the development of sigma(2) receptor agonists as novel therapeutic drugs for treating cancer. Consequently, sigma(2) receptor ligands have been demonstrated to be potentially useful tumor imaging ligands. In this article, we focus on the sigma receptor ligands as therapeutic agents and as radiopharmaceuticals.     

Studies on 18F-labeled pyrimidines III. Biochemical investigation of 18F-labeled pyrimidines and comparison with 3H-deoxythymidine in tumor-bearing rats and mice

Metabolic studies of 18F-labeled 5-fluoro-2'-deoxyuridine(FdUrd), 5-fluorouridine(FUrd) and 5-fluorouracil (FUra) were performed in tumor-bearing rats and mice. Also, the usefulness of 18F-FdUrd and 3H-deoxythymidine (dThd) for tumor detection was compared. In the tumor, 2 h after the injection of the 18F-pyrimidines, 3%-11% and 6%-14% of the 18F was present in the nuclear and microsomal fractions, respectively, and 17%-34% and 19%-24% of the 18F was incorporated into the acid-insoluble and nucleotide fractions, respectively. Of the three 18F-pyrimidines, 18F-FUrd demonstrated the highest incorporation rate, while 18F-FUra showed the lowest incorporation rate. The incorporation in the spleen, small intestine, and liver was less than that in the tumor. 3H-dThd and 18F-FdUrd were injected into the same mice. The 3H-dThd was accumulated in the spleen, small intestine, and tumor, and in these three tissues significant amounts of the 3H were incorporated into acid-insoluble materials. However, the clearance of 18F-FdUrd was slow in the tumor but rapid in the spleen and small intestine. In the autoradiograms of the tumor, 18F and 3H showed a slightly different distribution. Both distribution patterns were unchanged when the soluble materials were rinsed out with perchloric acid. For tumor detection, 18F-FdUrd gives the same information as radio-dThd, and further information can be obtained by positron-emission tomography.     

Placental transfer of positron-emitting radionuclides in metabolic substrates

Experimental studies on the biodistribution and placental transfer of in vivo metabolic constituents in pregnant rats were investigated with positron-emitting compounds such as 18F-2-fluoro-2-deoxyglucose, a mixture of 11C-glucose and 11C-fructose, 11C-L-methionine, 11C-D,L-leucine, 11C-adenine, 18F-5-fluoro-2'-deoxyuridine, 11C-S-adenosyl-L-methionine and 11C-coenzyme Q10. Sugars and amino acids transferred easily through the placenta and distributed into the fetal tissues to a similar extent as into the maternal tissues. The fetus-to-placenta ratios for the amino acids were always over 1.0, which indicated active transport of the amino acids in the placenta. On the contrary, other compounds have some limitation to transfer through the placenta in comparison with the sugars and amino acids. The fetus-to-placenta ratios of 11C-adenine, 11C-S-adenosyl-L-methionine and 11C-coenzyme Q10 were much less than the placenta-to-blood ratios, which indicated the presence of a certain placental barrier against these compounds. 11C-S-adenosyl-L-methionine and 11C-coenzyme Q10 were incorporated more into the fetal brain than into the maternal brain which is probably due to the nutritional requirement of the fetal brain and/or an immature blood-brain barrier.     

Studies on 18F-labeled pyrimidines. Tumor uptakes of 18F-5-fluorouracil, 18F-5-fluorouridine, and 18F-5-fluorodeoxyuridine in animals

Three 18F-labeled pyrimidines, 18F-5-fluorouridine (18F-5-FUR), 18F-5-fluorouracil (18F-5-FU), and 18F-5-fluorodeoxyuridine (18F-5-FdUR), were examined regarding tissue distribution and tumor uptake in ascitic hepatoma AH109A-bearing rats. The differential absorption ratios of tumors of 18F-5-FUR, 18F-5-FU, and 18F-5-FdUR were 0.75 +/- 0.21, 0.92 +/- 0.15, and 0.96 +/- 0.24 at 30 min, and 0.37 +/- 0.09, 0.64 +/- 0.34, and 0.60 +/- 0.17 at 120 min, respectively. The tumor-to-organ ratios obtained with three radiopharmaceuticals, especially with blood, heart, lung, muscle, and brain were high and these ratios increased with time. The tumor-to-organ ratios obtained with 18F-5-FdUR were always 1.3-4 times higher than 18F-5-FU and 18F-5-FUR. We concluded that 18F-5-FdUR was a suitable radiopharmaceutical for tumor imaging. Positron emission tomography of a rabbit tumor located on the chest with 18F-5-FdUR clearly showed the tumor within 1 h.     

The clinical value of urinary polyamine analysis in urological disease

To study the clinical usefulness of the determination of urinary polyamine levels, voluntary urine of several urological diseases including 56 bladder tumor patients was analyzed by high performance liquid chromatography. The obtained values were adjusted by the concentration of urinary creatinine and expressed as the unit of mumol/g creatinine (mumol/g Cr) From the measurement of 8 normal adults, the normal upper limit of each polyamine was decided by mean + 2SD, and the limit for total polyamine was 59.1 mumol/g Cr, putrescine 38.1 mumol/g Cr, spermidine 16.6 mumol/g Cr and spermine 9.2 mumol/g Cr, respectively. In the patients with non-neoplastic benign urological disease, the polyamine levels were statistically not different from those of the normal adults. In the case of bladder tumor, the urinary levels of total polyamine, putrescine and spermine were significantly elevated compared with the control group. The true positive rate of this determination in bladder tumor patients was 26/56 (46%) by total polyamine level, 21/56 (38%), by putrescine level, 11/56 (56%) by spermidine level and 16/56 (29%) by spermine level. Grade or stage of the bladder tumor did not have any significant correlation with the urinary polyamine level. This determination would not be included in routine clinical examinations due to the difficulty of measurement, difference of urine sampling and lack of high sensitivity and specificity.     

Solitary ureteral metastasis from cervical cancer: a case report

A case of solitary ureteral metastasis from cervical cancer in a 36-year-old female is reported. On April 4, 1988, the patient visited the gynecological department of our hospital with abnormal genital bleeding. Colposcopy and cervical biopsy revealed invasive cervical cancer, and computerized tomography (CT) indicated right hydronephrosis. She was referred to the urological department for further examinations. Right retrograde pyelography (RP) however could not be performed. On April 13, 1988, the patient underwent laparotomy due to acute abdomen, which was proved to be caused by subileus. On exploration, a tumor was found in the lower one third section of the right ureter, whereupon a right nephroureterectomy was performed because primary ureteral tumor was suspected. The histology of the ureteral tumor revealed it to be a metastatic squamous cell carcinoma identical to that obtained from punch biopsy of the cervix. At that time, a hysterectomy could not be done because of invasive cervical cancer. Following the operation, radiation therapy was conducted for primary cervical cancer. At present, 7 months after the operation, the patient is alive with good performance status.     

Local regulation of neutrophil elastase activity by endogenous α1-antitrypsin in lipopolysaccharide-primed hematological cells

Neutrophil elastase released from activated neutrophils contributes in combating bacterial infection. While chronic inflammation results in anemia and decreased bone marrow activities, little is known about the effect of neutrophil elastase on hematological cell growth in severe inflammatory states. Here, we demonstrated that α1-antitrypsin, a physiological inhibitor of neutrophil elastase, functions as a regulator for cell growth by neutralizing neutrophil elastase activity in lipopolysaccharide-primed hematological cells. HL-60 cells were resistant to neutrophil elastase, as they also expressed α1-antitrypsin. The growth of HL-60 cells transduced with a LentiLox-short hairpin α1-antitrypsin vector was significantly suppressed by neutrophil elastase or lipopolysaccharide. When CD34⁺ progenitor cells were differentiated towards a granulocytic lineage, they concomitantly expressed neutrophil elastase and α1-antitrypsin and prevented neutrophil elastase-induced growth inhibition. These results suggest that granulocytes might protect themselves from neutrophil elastase-induced cellular damage by efficiently neutralizing its activity through the simultaneous secretion of endogenous α1-antitrypsin.