cysteinyldopa and Neoplasm-Metastasis

5-S-Cysteinyldopa (5-S-CD) has been used as a biochemical marker of melanoma progression. In this study, we measured serum levels of 5-S-CD in 2648 samples taken from 218 patients in order to evaluate the usefulness of this parameter in following melanoma progression and prognosis. 5-S-CD levels were significantly elevated above the upper limit of the normal range (10 nmol/l) in stage IV melanoma patients. The sensitivity of elevated serum 5-S-CD levels in detecting distant metastasis was 73%, while the specificity was 98% and the positive predictive value 94%. The sensitivity was improved to 77% when cases of amelanotic melanoma were excluded. Patients without metastases had elevated 5-S-CD values in 5% of the 1480 serum samples. Changes in serum 5-S-CD levels were followed during disease progression until the end stage in 49 patients. In 33% of the patients, elevation of serum 5-S-CD levels preceded clinical detection of visceral metastases, and in 37% elevation of 5-S-CD levels occurred at the same time as visceral metastasis. Patients with elevated 5-S-CD levels before or after surgical treatment had significantly shorter survival times than those with normal levels. These results show that the level of 5-S-CD in the serum is a sensitive and specific marker in predicting distant metastases. Elevated serum levels of 5-S-CD, before or after surgical treatment, is associated with a poor prognosis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Child; Cysteinyldopa; Disease Progression; Eye Neoplasms; Female; Follow-Up Studies; Humans; Japan; Life Tables; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Sensitivity and Specificity; Skin Neoplasms; Survival Analysis

Serum S-100 protein is widely used as a marker of melanoma and since 5-S-cysteinyldopa (5-S-CD) is a precursor of melanin its serum and urinary levels can reflect melanoma progression. In this study we examined the concentration changes of serum S-100 protein and 5-S-CD in 252 melanoma patients of different clinical stages. Serum samples were taken from 252 melanoma patients at 860 times, from June 1996 to July 1998. The serum S-100 protein was measured by the immunoluminometric assay, levels of 5-S-CD was determined by HPLC. The value of S-100 protein in patients with primary melanoma (0.11m mg/l) and in patients without symptoms (0.15 m mg/l) ranged around the normal level (0.01 0.12 m mg/l). There was a significant difference between the values of patients with or without symptoms. There was a similarly significant difference between the S-100 values of clinical Stage I (0.11 mg/l) and Stage III (2.91 mg/l) as well as between those of clinical Stage II (0.47 mg/l) and Stage III (2.91 mg/l), respectively. Analyzing the values of patients with symptoms we observed significant difference between the S-100 protein values of patients with primary tumor and those with solitary or multiple distant metastases. In case of 5-S-CD significant difference was found between clinical Stage I and III as well as clinical Stage II and III. Furthermore, there was a significant difference between the mean marker values of patients with primary tumor, lymph node, lung metastasis and clinical stage III.

Topics: Biomarkers, Tumor; Cysteinyldopa; Disease Progression; Disease-Free Survival; Humans; Liver Neoplasms; Lung Neoplasms; Lymph Nodes; Melanins; Melanoma; Models, Biological; Neoplasm Metastasis; S100 Proteins; Skin Neoplasms

Urinary excretion of 5-S-cysteinyldopa (5-S-CD) has been used as a biochemical marker of melanoma progression. Melanomas produce not only 5-S-CD but also 5,6-dihydroxyindole-2-carboxylic acid (5,6DHI2C) as major intermediates in melanin formation. 5,6DHI2C is then metabolized to the two O-methyl derivatives, 5H6MI2C and 6H5MI2C. The aim of this study was to determine which marker in serum and urine most sensitively reflected the progression of melanoma.. Serum and 24-hour urine samples were collected and assayed serially by high-performance liquid chromatography every 1 to 4 months in 28 patients with primary or recurrent melanomas, for up to 48 months.. Serum concentration and urinary excretion of 5-S-CD and 6H5MI2C in patients with melanoma without metastases were close to those obtained from normal subjects. Metastases developed in 9 of the 28 patients. In seven of these nine patients, serum or urinary 5-S-CD values were elevated before or at the time of clinical detection of visceral metastases. However, serum 5-S-CD was elevated significantly earlier and reflected melanoma progression better than the physical examination and/or laboratory tests, such as scintigraphy and echography. Serum 6H5MI2C values exceeded the normal range shortly before death in three patients, and urinary 6H5MI2C did not increase at any stage in most patients, therefore these metabolites did not reflect progression of disease.. Among the four markers, serum 5-S-CD appears to be the best biochemical marker for the detection of progression of melanotic melanoma, a value of more than 10 nmol/l suggesting the presence of metastasis.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Chromatography, High Pressure Liquid; Cysteinyldopa; Female; Humans; Indoles; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Skin Neoplasms

A sensitive assay method employing high performance liquid chromatography with electrochemical detection (HPLC-ED) was used to compare 5-S-cysteinyldopa (CD) levels in plasma to tumor size in a murine melanoma model system. Plasma CD levels correlated with the sizes of primary tumor masses in mice, and the presence of metastatic tumors did not significantly affect the relationship. Elevated plasma CD levels appear to be directly related to tumor pigmentation: mice who had nonpigmented tumors induced by injections of amelanotic melanoma cells (NP) did not have elevated plasma CD levels. These studies indicate that plasma CD levels may serve as a marker for pigmented malignant melanomas and may be useful in following patients who are at high risk for these tumors.

Topics: Animals; Cysteinyldopa; Dihydroxyphenylalanine; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Tumor Cells, Cultured

In case of uncharacteristic patient complaints or slightly pathologic BSR or liver enzyme levels in patients, suffering from melanoma, the determination of 5-S-cysteinyldopa in the 24-h-urine may be of great diagnostic value. If the complaints and the pathologic values are early symptoms and signs of generalized metastases being clinically not yet manifest, the excretion of 5-S-cysteinyldopa in the urine is often increased. In such cases, a thorough and possibly invasive search for metastases is indicated.

Topics: Cysteinyldopa; Dihydroxyphenylalanine; Humans; Isomerism; Melanoma; Neoplasm Metastasis; Skin Neoplasms

This study examines 5-S-cysteinyldopa, which is a melanoma-associated marker, and sialic acid whose increase appears to be a common feature of numerous cancers. In spite of some interferences due to sun exposure, 5-S-cysteinyldopa seems a significant indicator of metastases; the difference between 46 metastasis-negative and 34 metastasis-positive melanomas is significant at P less than 0.001. Cerebral metastases give little or no increase. In contrast with the 75% of patients who keep normal 5-S-cysteinyldopa excretion, all melanoma patients have elevated sialic acid. No difference occurs between glycoprotein carbohydrates of controls and patients after pronase digestion and con A chromatography. The use of those two parameters in association is proposed to have a proper index of tumor burden or success of therapy.

Topics: Adult; Aged; Cysteinyldopa; Dihydroxyphenylalanine; Female; Humans; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Sialic Acids

In a total of 1,828 determinations, urinary excretion of 5-S-Cysteinyldopa was studied over a period of three years in 384 patients treated for melanoma or with metastases of malignant melanoma. By serial investigations the excretion of 5-S-Cysteinyldopa was compared to the course of the disease. In the case of small and circumscribed metastases which could be eliminated by surgical treatment, the excretion of 5-S-Cysteinyldopa remained normal. When the disease became generalized, an increase of the urinary excretion of 5-S-Cysteinyldopa prior to the clinical manifestation of the metastases was observed in only four out of 26 cases. In the remaining cases, the increase of 5-S-Cysteinyldopa coincided with the manifestation of metastases, or the excretion of the substance became pathological when the metastases were already conspicuous. In five patients, the urinary excretion of 5-S-Cysteinyldopa remained normal inspite of widespread disease. Therefore, its diagnostic value seems to be similar to that of the "common" laboratory investigations the results of which are only pathological when the disease has already become generalized. Our investigations demonstrate that serial investigations of the urinary excretion of 5-S-Cysteinyldopa only rarely indicate melanoma metastases prior to their clinical manifestation. In cases of early metastasing melanoma, all common laboratory investigations are of limited value. BSR and GGT levels which become pathological very early in the course of the disease are so sensitive that slightly pathological levels may be ambiguous. In these cases, however, pathological levels of 5-S-Cysteinyldopa most probably will indicate a widespread disease.

Topics: BCG Vaccine; Cysteinyldopa; Dihydroxyphenylalanine; Female; Humans; Male; Melanoma; Melphalan; Neoplasm Metastasis; Skin Neoplasms

Of 16 cell lines derived from 12 human melanomas obtained from 11 patients, all were established as permanent cell lines: 7 from primary tumors and 9 from metastatic tumors. Study of the early subcultures and established cell lines showed that melanocytes passed through a phase of dedifferentiation during which they took on a fibroblast-like appearance and were hypodiploid and nontumorigenic in nude (thymus-deficient) mice. Phenotypic modulation in vitro was shown to be dependent on the culture medium. The lines varied considerably in karyologic and phenotypic expression (as assessed by morphologic appearance and 5-S-cysteinyldopa production). Fibroblast-like, epithelioid, nonpigmented, achromic, and pigmented cells were obtained from the same tumor. Heterotransplantation into nude mice revealed wide variations in tumorigenicity: The latency of the tumors, their size, and infrequent metastases bore no relationship to the phenotypic modulation of the melanocytes as expressed in vitro. Melanogenesis is therefore not related to malignancy; they are two independent characteristics.

Topics: Animals; Cell Differentiation; Cell Line; Culture Media; Cysteinyldopa; Female; Humans; Male; Melanocytes; Melanoma; Mice; Mice, Nude; Microscopy, Electron; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Phenotype; Skin Neoplasms; Transplantation, Heterologous

Determinations of the urinary excretion of 5-S-cysteinyldopa were performed in 571 patients previously treated by surgery for melanoma or melanoma metastasis. 90% of the 161 patients with metastases showed values exceeding 0.15 mg/24 h, and 9% of the 410 patients without metastases had such values. The increase in 5-S-cysteinyldopa excretion was generally more pronounced in men with metastases than in women, 98% of the men and 77% of the women with metastases showing values exceeding 0.15 mg/24 h. High levels of 5-S-cysteinyldopa are of grave prognostic significan4% died within one month, and only 3% survived for more than a year. In Sweden, determination of 5-S-cysteinyldopa in patients operated on for melanoma gives maximum information in the winter (October--March), when sun exposure does not influence the excretion levels.

Topics: Adult; Aged; Cysteinyldopa; Dihydroxyphenylalanine; Female; Hair Color; Humans; Lymphatic Metastasis; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Sex Factors; Skin Neoplasms; Sunlight

The relationships between differentiation and malignant transformation were studied in human malignant melanomas in vivo and in vitro. Melanocyte differentiation was assessed by ultrastructural morphological characteristis (the appearance of the melanosomes and related structures) localization of dopa-oxidase and assay of 5-S-cysteinyldopa, a specific metabolite. The transformed characteristic of the cells in vitro was evaluated by their ability to give rise to established cell lines, karyological modifications and heterotransplantation in Nude mice and Syrian hamsters. Morphological variability of the cells in malignant melanomas is accompanied by variability in the localization of dopa-oxidase, the level of 5-S-cysteinyldopa, chromosome pattern and their heterotransplantibility. The lack of pigmentation in some malignant melanoma lines can result from either an irreversible loss of some functions which give rise in melanization and the malignancy in maintained, or by phenomenon of regulation determined by intra or extra-cellular factors with the loss of heterotransplantability. Modulation phenomena affecting tumorigenicity and pigmentation although sometimes concomitant are not identical.

Topics: Animals; Cell Differentiation; Cell Transformation, Neoplastic; Chromosome Mapping; Cricetinae; Cysteinyldopa; Humans; Melanocytes; Melanoma; Mesocricetus; Mice; Mice, Nude; Monophenol Monooxygenase; Neoplasm Metastasis; Neoplasm Transplantation

Determination of urine cysteinyldopa excretion is the most sensitive chemical test for the detection of melanoma metastases and has been successfully applied during the Scandinavian winter, when sun irradiation is low. The value of this determination, under Australian conditions of greater sun irradiation, has been assessed by comparing the cysteinyldopa excretion of patients with that of normal subjects exposed to sunlight. Cysteinyldopa is an intermediate in the biosynthesis of the red-brown phaeomelanin. Of 20 patients without known secondary melanoma, the cysteinyldopa concentration of "spot" urines ranged from 0 to 190 (mean 48) microgram/ml; of six known to have local metastases, 0 to 80 (mean 19) microgram/ml; and of four known to have extensive metastases 80 to 1350 (mean 330) microgram/ml. The effect of sun irradiation alone was assessed in nine healthy subjects followed one to 11 weeks before and after recorded periods of sun exposure. The cysteinyldopa concentrations of 24-hour urines ranged from 40 to 3100 microgram/ml. Increases occurred three to 10 days following sun exposure and were greatest following multiple small exposures in an individual with "Celtic" complexion. It is concluded that measurement of cysteinyldopa concentration would be of value in the follow-up of melanoma patients in Australia only if patients could be persuaded to live under conditions free of all direct sun-irradiation.

Topics: Adolescent; Adult; Australia; Cysteinyldopa; Dihydroxyphenylalanine; Humans; Melanoma; Neoplasm Metastasis; Skin Neoplasms; Sunlight

The urine of patients with melanoma metastases and increased urinary excretion of 5-S-cysteinyldopa was examined for trichochromes. Five of 16 patients showed urinary excretion of trichochromes B and C. None excreted trichochromes E or F. All patients showing trichochrome excretion had very large amounts of cysteinyldopa in their urine.

Topics: Adult; Aged; Cysteinyldopa; Female; Hair Color; Humans; Male; Melanins; Melanoma; Middle Aged; Neoplasm Metastasis; Skin Neoplasms

27 patients with SSM or NM level IV and V have been submitted to a monthly evaluation of their level of 5-S-cysteinyldopa in the urine and IgG4 subclass in their sera. For 5 patients who entered the stage II of their disease during the follow-up, 3 had elevation of the 5S and 5 had large variations of IgG4. On 21 patients in clinical remission, 10 had conjunctly an increase of 5S and variations of IgG4. The predictional value of these tests is discussed.

Topics: Cysteinyldopa; Dihydroxyphenylalanine; Humans; Immunoglobulin G; Melanoma; Neoplasm Metastasis

Topics: Cysteinyldopa; Dihydroxyphenylalanine; Humans; Melanoma; Neoplasm Metastasis; Skin Neoplasms

A newly discovered amino acid, 5-S-cysteinyldopa, present in the urine of healthy subjects is excreted in pathological amounts in many patients suffering from melanoma metastases. Increased excretion of 5-S-cysteinyldopa may be observed before metastases become clinically evident. Determination of 5-S-cysteinyldopa is superior to determination of dopa+dopamine in the diagnosis of melanoma metastases.

Topics: Adult; Aged; Cysteinyldopa; Dihydroxyphenylalanine; Eye Neoplasms; Female; Humans; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Skin Neoplasms

Topics: Adult; Aged; Cysteinyldopa; Dihydroxyphenylalanine; Dopamine; Female; Humans; Male; Melanoma; Microscopy, Electron; Middle Aged; Neoplasm Metastasis

Topics: Cysteinyldopa; Dihydroxyphenylalanine; Humans; Melanoma; Neoplasm Metastasis

By using ion-exchange column chromatography with effluent monitoring using the stable, free radical alpha,alpha-diphenyl-beta-picryhydrazyl as a colorimetric reagent, we have demonstrated the occurrence of elevated levels of five peaks in the urine of patients with metastatic disease. The tentative assignment of two of the peaks as 3,4-dihydroxyphenylalanine and as 3-methoxy-4-hydroxyphenylalanine has been made. Three remain unknown. The correlation of these peaks with the clinical status of melanoma patients shows that, while the individual excretion pattern of these compounds may be variable, the sustained occurrence of one or more of them in a patient's urine is evidence of recurrent or continuing disease. The excretion levels appear to be proportional to the tumor burden. The results with a group of 39 melanoma patientshaving Stage II or Stage III disease indicate that this chromatography technique provides earlier evidenc eof liver metastases than doses the liver scan, may detect occult metastases generally, and has detected tumor in clinically enlarged lymph nodes. This method, in its present form, does not detect small pulmonary lesions earlier than chest X-ray or tomography do or brain metastases earlier than do brain scan or computerized axial tomography. The technique is clinically useful for the diagnosis of melanoma patients and in their follow-up while under treatment.

Topics: Chromatography, Ion Exchange; Cysteinyldopa; Dihydroxyphenylalanine; Female; Humans; Male; Melanoma; Methyldopa; Neoplasm Metastasis