With the recent development of novel molecular targeted drugs for advanced stage malignant melanoma (MM), including RAF and mitogen-activated protein kinase kinase inhibitors and immune checkpoint ...blockers, the early detection of relapse is important for managing patients with MM. In this study, we retrospectively analyzed two conventional serum biomarkers, 5-S-cysteinyl-dopa and lactate dehydrogenase, in patients with MM (n = 140) who were treated at a single Japanese institute from June 2007 to June 2015. At the initial hospital visit, serum 5-S-cysteinyl-dopa levels were significantly increased in patients with stages III (n = 38) and IV (n = 20) MM compared with patients with stages 0-II (n = 62) MM. In addition, in patients with stages III and IV MM, serum 5-S-cysteinyl-dopa levels of more than 15.0 nmol/L at initial hospital visit correlated with a poor prognosis. In 11 of 14 patients whose disease progressed during follow up (mostly from stages III-IV), serum 5-S-cysteinyl-dopa levels exceeded the normal limit of 10.0 nmol/L during the clinical detection of distant metastases. These results indicate the usefulness of measuring serum 5-S-cysteinyl-dopa levels at initial hospital visit and during follow up for early and effective therapeutic interventions using newly developed molecular targeted drugs.
Neurocutaneous melanosis（NCM）is a rare congenital disease caused by proliferation of melanocytes in the skin and central nervous system. The prognosis is poor if neurological symptoms develop. In ...this paper, we report a four-day-old boy who had a giant pigmented nevus at birth. High-intensity lesions on magnetic resonance imaging（MRI）T1-weighted images of brain tissue including the amygdala suggested melanocytic proliferation in the central nervous system and we diagnosed this case as NCM from a remarkably elevated level of serum 5-S-cycteinyldopa（5-S-CD）. Although pathological findings in the central nervus system or neurological symptoms are necessary for the definitive diagnosis of NCM, recent reports indicated that NCM is often diagnosed by the combination of giant pigmented nevi and brain MRI findings. In addition to the giant pigmented nevi and MRI finding including T1-high intensity lesions or leptomeningeal gadolinium-enhancement, melanocytes in cerebrospinal fluid or remarkably high levels of 5-S-CD in cerebrospinal fluid or serum suggestive of melanocyte proliferation in the central nervus system would improve the accuracy of the diagnosis. Early diagnosis of NCM during the neonatal period makes it possible to support the family psychologically and provide early intervention for central nervous system disorders.
Neurocutaneous melanosis is caused by postzygotic NRAS mutations in neural crest cells, resulting in large or multiple nevi in the skin and proliferation of leptomeningeal melanocytes in the central ...nervous system. The onset of neurological symptoms is usually before the age of 2 years, but it can also occur in adults. A 35-year-old male had been asymptomatic for a long time after excision of a large congenital melanocytic nevus, but he developed headache, disturbance of consciousness, and seizure. Methotrexate was ineffective, cerebral pressure was decreased by spinal drainage, and steroid pulse therapy was temporarily effective. Seizures and disturbance of consciousness worsened and the patient died on the 92nd day. Cerebrospinal fluid human melanin black-45 immunostaining and serum 5-S-cysteinyldopa (5-S-CD) were useful in diagnosing melanocytic proliferation, and serum 5-S-CD may be useful in predicting prognosis.
Melanoma is one of the most lethal and malignant cancers and its incidence is increasing worldwide, and Japan is not an exception. Although there are numerous therapeutic options for melanoma, the ...prognosis is still poor once it has metastasized. The main concern after removal of a primary melanoma is whether it has metastasized, and early detection of metastatic melanoma would be effective in improving the prognosis of patients. Thus, it is very important to identify reliable methods to detect metastases as early as possible. Although many prognostic biomarkers (mainly for metastases) of melanoma have been reported, there are very few effective for an early diagnosis. Serum and urinary biomarkers for melanoma diagnosis have especially received great interest because of the relative ease of sample collection and handling. Several serum and urinary biomarkers appear to have significant potential both as prognostic indicators and as targets for future therapeutic methods, but still there are no efficient serum and urinary biomarkers for early detection, accurate diagnosis and prognosis, efficient monitoring of the disease and reliable prediction of survival and recurrence. Levels of 5-
-cysteinyldopa (5SCD) in the serum or urine as biomarkers of melanoma have been found to be significantly elevated earlier and to reflect melanoma progression better than physical examinations, laboratory tests and imaging techniques, such as scintigraphy and echography. With recent developments in the treatment of melanoma, studies reporting combinations of 5SCD levels and new applications for the treatment of melanoma are gradually increasing. This review summarizes the usefulness of 5SCD, the most widely used and well-known melanoma marker in the serum and urine, compares 5SCD and other useful markers, and finally its application to other fields.
Rat kidney glutamine transaminase K (GTK) exhibits broad specificity both as an aminotransferase and as a cysteine S-conjugate β-lyase. The β-lyase reaction products are pyruvate, ammonium and a ...sulfhydryl-containing fragment. We show here that recombinant human GTK (rhGTK) also exhibits broad specificity both as an aminotransferase and as a cysteine S-conjugate β-lyase. S-(1,1,2,2-Tetrafluoroethyl)-l-cysteine is an excellent aminotransferase and β-lyase substrate of rhGTK. Moderate aminotransferase and β-lyase activities occur with the chemopreventive agent Se-methyl-l-selenocysteine. l-3-(2-Naphthyl)alanine, l-3-(1-naphthyl)alanine, 5-S-l-cysteinyldopamine and 5-S-l-cysteinyl-l-DOPA are measurable aminotransferase substrates, indicating that the active site can accommodate large aromatic amino acids. The α-keto acids generated by transamination/l-amino acid oxidase activity of the two catechol cysteine S-conjugates are unstable. A slow rhGTK-catalyzed β-elimination reaction, as measured by pyruvate formation, was demonstrated with 5-S-l-cysteinyldopamine, but not with 5-S-l-cysteinyl-l-DOPA. The importance of transamination, oxidation and β-elimination reactions involving 5-S-l-cysteinyldopamine, 5-S-l-cysteinyl-l-DOPA and Se-methyl-l-selenocysteine in human tissues and their biological relevance are discussed.
: Oxidation of l‐3,4‐dihydroxyphenylalanine (l‐DOPA) and dopamine (DA) to generate semiquinones/quinones, oxygen radicals, and other reactive oxygen species may play a role in neuronal cell death in ...Parkinson's disease (PD). In particular, semiquinones/quinones can form conjugates with thiol compounds such as GSH and cysteine. Exposure of l‐DOPA, DA, and other catecholamines to a system generating O2•− radical led to O2•−‐dependent depletion of added GSH (or cysteine), accompanied by the formation of thiol‐DA or ‐DOPA adducts as detected by HPLC. Superoxide could additionally cause destruction of these adducts. Iron or copper ions could also promote conjugate formation between GSH or cysteine and DA and l‐DOPA, especially if H2O2 was present. We applied HPLC to measure glutathionyl and cysteinyl conjugates of l‐DOPA, DA, and 3,4‐dihydroxyphenylacetic acid (DOPAC) in postmortem brain samples from PD patients and normal control subjects. Conjugates were detected in most brain areas examined, but levels were highest in the substantia nigra and putamen. In most regions, adduct levels were lower in PD, but there were significant increases in cysteinyl adducts of l‐DOPA, DA, and DOPAC in PD substantia nigra, suggesting that acceleration of l‐DOPA/DA oxidation occurs in PD, although we cannot say if this is a primary feature of the disease or if it is related to therapy with l‐DOPA. In vitro, conjugate formation could be inhibited by the dithiol dihydrolipoate but not by its oxidised form, lipoic acid.
Introduction
We herein present a case of malignant melanoma of the male urethra with an increased serum 5‐S‐cysteinyldopa concentration.
Case presentation
A 77‐year‐old man visited our hospital ...complaining dysuria and a dark brown mass protruding from the external urethral meatus. His serum 5‐S‐cysteinyldopa concentration was elevated beyond the upper limit of the reference range. Biopsy of the tumor was performed, and the histological diagnosis was malignant melanoma. He underwent total penectomy, and the serum 5‐S‐cysteinyldopa concentration was normalized. He remained alive without evidence of locoregional recurrence or distant metastases for 6 months after surgery.
Conclusion
Malignant melanoma of the male urethra is uncommon. The prognosis is favorable if it is detected in its early stages. This case report suggests that measurement of the serum concentration of 5‐S‐cysteinyldopa, a melanin metabolite, is useful for early diagnosis of male urethral melanoma.
Human glutathione transferase M2-2 prevents the formation of neurotoxic aminochrome and dopachrome by catalyzing the conjugation of dopamine and dopa o-quinone with glutathione. NMR analysis of ...dopamine and dopa o-quinone-glutathione conjugates revealed that the addition of glutathione was at C-5 to form 5-S-glutathionyl-dopamine and 5-S-glutathionyl-dopa, respectively. Both conjugates were found to be resistant to oxidation by biological oxidizing agents such as O2, H2O2, and O•−2, and the glutathione transferase-catalyzed reaction can therefore serve a neuroprotective antioxidant function.
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