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K Jimbow

Publications and source records attributed to K Jimbow.

At least 91 records · Page 5Linked to original sources
PubMed1992

Regulatory factors of pheo- and eumelanogenesis in melanogenic compartments.

Melanogenesis, i.e., synthesis of melanin and melanosomes, is a "cascade" of event which is channelled by internal and external regulatory factors. The recognition and selection of this information and subsequent differentiation of melanogenesis (melanin type and melanosomal development) would be regulated significantly by melanosomal membrane. The melanogenesis type could be switched relatively easily by UV light, hormone, and availability of tyrosinase substrate. The role of sulphydryl compounds as a regulatory factor in melanogenesis type (in particular for pheomelanogenesis) may not be tied to its absolute presence or absence, but rather, to the effective concentration within the melanocyte at a given time. It is, therefore, probable that the morphogenesis of melanosomes may not follow immediately in response to melanogenesis-type changes, hence the melanocyte revealing more often mosaic forms of melanosomes in nature after exposure to non-genetic factors. The switch of melanogenesis would be significantly controlled by structural and functional availability of vesiculoglobular bodies which are encoded or associated with HMSA-5 (69 kDa) glycoprotein. This HMSA-5 protein shares a significant homology with gp75 "b-locus" protein. However, because of our hypothesis that vesiculoglobular bodies carry post- (and pre-) tyrosinase regulatory factors involving in both pheo- and eumelanogenesis, the term "b-protein" which focuses only on eumelanogenesis may not be applied to HMSA-5.

Animals↗
PubMed1992

Measurement of eumelanin precursor metabolites in the urine as a new marker for melanoma metastases.

BACKGROUND AND DESIGN: This article introduces a rapid high-performance liquid chromatographic assay to measure urinary pheomelanin and eumelanin metabolites, 5-S-cysteinyldopa and indoles, 5(6)-hydroxy-6(5)-methoxyindole-2-carboxylic acid. RESULTS: Our high-performance liquid chromatographic study clearly showed (1) urine of melanoma patients with positive metastasis revealed significant amounts of 5-S-cysteinyldopa and indoles (5,6-dihydroxyindole-2-carboxylic acid plus 6-hydroxy-5-methoxyindole-2-carboxylic acid) above 1 mumol/d and 2 mumol/d, respectively; and (2) in patients with metastasis-free melanoma these melanin metabolites might be excreted into the urine but always less than the two values cited above. CONCLUSIONS: As there is a discrepancy regarding the specificity of 5-S-cysteinyldopa as a marker for estimation of melanoma metastasis, high-performance liquid chromatographic measurement of urinary indoles will provide an additional assay in the detection of melanoma metastasis from an early stage. Both melanoma markers were increased in the urine of patients with metastatic melanoma.

Adult↗
PubMed1991

Tyrosine transport in a human melanoma cell line as a basis for selective transport of cytotoxic analogues.

Tyrosine is an essential amino acid for the initial step of melanin synthesis, yet little is known concerning its transport in melanocytes. As an important first step in the development of new anti-melanoma agents based upon chemical and pharmacological modifications of melanin synthesis, the present study characterized the transport mechanism of tyrosine in vitro using the human melanoma cell line SK-MEL 23. Several tyrosine transport systems may be involved in melanocytes: systems L and T, which transport neutral amino acids with branched or aromatic side chains, and systems A and ASC, which transport neutral amino acids with smaller side chains. In order to determine which system or combination of systems is involved in tyrosine transport in melanoma cells, studies of kinetics, Na(+)-dependence and competitive inhibition were undertaken. The Km and Vmax. for the Na(+)-independent transport system were found to be 0.164 +/- 0.016 mM and 21.6 +/- 1.1 nmol/min per mg of protein respectively. This transport was preferentially inhibited by the system L specific analogue, 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid, the system T substrate tryptophan, and the sulphur homologue of tyrosine, 4-S-cysteinylphenol. Sequential addition of these inhibitors at increasing concentrations indicated that they inhibit the same transporter. Our results suggest that tyrosine transport in SK-MEL 23 melanoma cells is similar to system L transport previously characterized in other cell types. This one transport system appears to supply all the tyrosine required for both cell growth and melanin synthesis. The transport system may be subject to manipulation by melanogenic stimulating factors, making the transport of cytotoxic tyrosine analogues an important area for further study.

Amino Acids↗
PubMed1991

Dysplastic melanocytic nevus. Immunohistochemical heterogeneity by melanosomal markers and S-100.

This study evaluates the expression of human melanosome specific antigen-1 and -2 (HMSA-1, -2) by dysplastic melanocytic nevus (DMN) and its significance by (a) immunostaining pattern, (b) other immunohistochemical markers (e.g., S-100), and (c) mesenchymal responses (e.g., lymphocytic infiltration). From 31 patients with DMN syndrome, 55 clinically characteristic and histologically (H&E) proven dysplastic nevi were assessed for HMSA expression. Approximately 70% of DMN lesions expressed the HMSA antigens; similar gross staining patterns were seen with both monoclonal antibodies (MoAbs). The expression of HMSA-2 was invariably associated with that of HMSA-1, but the converse did not apply. Two general staining patterns with MoAbs HMSA were appreciated: (a) uniform staining of the epidermal melanocytes in the DMN lesion (type I) and (b) nonuniform staining, with the epidermal melanocytes at the periphery of the DMN lesion reacting most intensely (type II). Although anti-S-100 antibody demonstrated a similar sensitivity (67%), it lacked specificity and did not distinguish different types of DMN, as compared with MoAbs HMSA. There was no correlation between these observed staining patterns and common histological features of DMN. There was a poor correlation between lymphocytic infiltrate (as judged by immunostaining for pan-T, Ti/h, Tc/s, and pan-B markers) and heterogeneity of immunostaining. We conclude that HMSA-1 and -2 are able to delineate two types of DMN and possibly bind different epitopes of the same antigen. Their potential usefulness in predicting malignant transformation of DMN has yet to be established.

Antibodies, Monoclonal↗
PubMed1991

The epidermal melanin unit in the pathophysiology of malignant melanoma.

The epidermal melanin unit (EMU) denotes the symbiotic relationship between a melanocyte and a pool of associated keratinocytes. We propose to show that alterations in the biology of the EMU are the main determinant of the different patterns of intraepidermal growth of melanocytes in lentigo maligna melanoma (LMM) and superficial spreading melanoma (SSM). They also appear to affect the biosynthesis of melanin and melanosomes during malignant transformation. Findings in histochemical studies with monoclonal antibodies generated against melanosomal proteins to produce different stains of melanocytes of normal skin, dysplastic melanocytic nevi (DMN), common melanocytic nevi (CMN), LMM, and SSM have led to the suggestion that the altered melanosome synthesis is a main phenotype in the pathophysiology in neoplastic transformation of melanocytes. Altered melanin synthesis may also affect the carcinogenesis in malignant melanoma: pheomelanin is increased in malignant melanoma and DMN, but not in normal skin and CMN. Pheomelanin and its precursors could aid the malignant transformation of melanocytes through the generation of mutagenic ultraviolet photoproducts in familial DMN syndrome.

Humans↗
PubMed1991

Selective cytotoxicity of N-acetyl-4-S-cysteaminylphenol on follicular melanocytes of black mice.

Previous in vivo studies have shown that 4-S-cysteaminylphenol (4-S-CAP) and N-acetyl-4-S-cysteaminylphenol (N-Ac-4-S-CAP) have antimelanoma effects and that N-Ac-4-S-CAP produced a 98% depigmentation of hair follicles of black mice. This study investigated the process of selective melanocytotoxicity by N-Ac-4-S-CAP through light and electron microscopy studies of hair follicles obtained from newborn black mice treated with N-Ac-4-S-CAP. Visible changes in follicular melanocytes were found 4 h after intraperitoneal (i.p.) administration. Clumps of melanin granules and areas of melanocytic nuclear condensation were seen in the hair follicles. On electron microscopy there was progressive destruction of melanocytes with swelling of membranous organelles, nuclear condensation, and vacuolation of the cytoplasm, culminating in completely necrotic cells. None of these changes were demonstrated in the surrounding keratinocytes. N-Ac-4-S-CAP appears to have specific, cytotoxic effects on melanocytes actively producing eumelanin. The drug may not affect precursor or dormant melanocytes which retain the ability to become active, melanin-producing cells.

Animals↗
PubMed1991

Lymphoid proliferation and lymphoma associated with human retroviruses (HTLV and HIV).

There are rapidly increasing opportunities for dermatologists to see patients suffering from retrovirus infections. The HTLV-I was the first class of human oncogenic retrovirus that was found in cultured cells of a patient with skin manifestations similar or identical to those of CTCL (MF). It was soon recognized as the agent causing ATLL. The skin manifestations, histopathology, and immunophenotypes of ATLL share many similarities with MF and SS. Both HTLV-I and HIV-I (HTLV-III) cause immunodeficiency with an increased susceptibility to opportunistic infections. Persistent generalized lymphadenopathies are the initial manifestations of most of the HIV infections. The incidence of lymphoid malignancies is expected to become much higher as the life span of AIDS patients is prolonged. They can have both B-cell and T-cell non-Hodgkin lymphomas, although the incidence of the latter (B-cell lymphoma) is still much higher than that of the former. All human retroviruses are transmitted in similar ways.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Dysplastic melanocytic nevi contain high levels of pheomelanin: quantitative comparison of pheomelanin/eumelanin levels between normal skin, common nevi, and dysplastic nevi.

The degree and type of melanogenesis, i.e., either eumelanin of pheomelanin, has been shown to be a reliable marker for the differentiation of the melanocyte. If exposed to UV light, these two melanins were reported to behave differently; eumelanin was photoprotective whereas pheomelanin was phototoxic to cultured tumor cells. Our previous study indicated that dysplastic melanocytic nevus (DMN) undergoes altered melanogenesis, forming pheomelanosome-like granules. The present study examined chemically the type and degree of melanin synthesized in 31 melanocytic nevi excised from 27 patients as compared with that occurring in the surrounding normal skin. The tissue content of eumelanin and pheomelanin was expressed by the amounts of pyrrole-2,3,5-tricarboxylic acid (PTCA) and aminohydroxyphenylalanine (AHP), respectively. We found that DMN lesions contain significantly higher amounts of pheomelanin than either common melanocytic nevus (CMN) or normal skin. Differences in pheomelanin content between DMN and CMN could not be accounted for by inherently higher levels of pheomelanin within the skin in general from DMN patients. Our present finding substantiates our previous claim that epidermal melanocytes in DMN undergo deranged melanogenesis.

Adolescent↗
PubMed1991

N-acetyl-4-S-cysteaminylphenol as a new type of depigmenting agent for the melanoderma of patients with melasma.

BACKGROUND AND DESIGN: --Melasma is a difficult medical problem to treat. Hydroquinone is administered to many patients, but it is unstable and local irritation and dermatitis may develop after a prolonged use at a high concentration. This study introduces a new depigmenting agent, N-acetyl-4-S-cysteaminylphenol, for better management of melanoderma in patients with melasma. RESULTS: --Our study, based on a retrospective observation of 12 patients using 4% N-acetyl-4-S-cysteaminylphenol in oil-in-water emulsion, showed a complete loss (8%), a marked improvement (66%), or a moderate improvement (25%) of melasma lesions. Visible changes of melanoderma can be seen in 2 to 4 weeks after daily topical application. This depigmentation was associated with a decrease in the number of functioning melanocytes and in the number of melanosomes transferred to keratinocytes. N-acetyl-4-S-cysteaminylphenol is the tyrosinase substrate, and, on exposure to tyrosinase, it formed a melanin-like pigment. CONCLUSIONS: --A phenolic thioether, N-acetyl-4-S-cysteaminylphenol, is a new type of depigmenting agent for the better management of melasma. It is much more stable and less irritating to the skin than hydroquinone, and it is specific to melanin-synthesizing cells.

Adult↗
PubMed1990

The in vivo antimelanoma effect of 4-S-cysteaminylphenol and its n-acetyl derivative.

Phenolic melanin precursors can be utilized for the development of anti-melanoma agents. The sulphur homologue of tyrosine, 4-S-cysteinylphenol (CP) and its decarboxylation product, 4-S-cysteaminylphenol (CAP) were shown to be substrates of melanoma tyrosinase, forming melanin-like pigment. Both, but in particular the 4-S-CAP, exhibited a significant in vivo depigmenting effect. Here, we report on the in vivo anti-melanoma effect of 4-S-CP, and 4-S-CAP and its N-acetyl derivative. In a previous in vitro study, it was shown that 4-S-CP and 4-S-CAP required a catalytic amount of dopa for optimal mammalian tyrosinase activity. To enhance the potential anti-melanoma effect of these two compounds. L-dopa and a decarboxylase inhibitor (carbidopa) were given concomitantly. We found that 4-S-CAP showed a significant growth inhibition of B16 melanoma inoculated s.c. into C57BL/6J mice. The anti-melanoma effect was increased significantly by combination of L-dopa and carbidopa. In addition, we tested the in vivo anti-melanoma effect of an N-acetyl derivative of 4-S-CAP (N-Ac-4-S-CAP). We found that N-Ac-4-S-CAP was the tyrosinase substrate and potent inhibitor of melanoma growth. N-acetyl 4-S-CAP showed a marked increase in water solubility. We suggest that N-Ac-4-S-CAP may prove to be a valuable model for the development of anti-melanoma agent using a metabolic pathway of melanin synthesis.

Animals↗
PubMed1990

Melanocytotoxicity and antimelanoma effects of phenolic amine compounds in mice in vivo.

A phenolic amine compound, 4-S-cysteaminylphenol (4-S-CAP), is a potent depigmenting agent. To develop more efficacious antimelanoma agents, we synthesized four homologues of 4-S-CAP: N-acetyl-4-S-CAP (N-Ac-4-S-CAP), alpha-methyl-4-S-CAP, 4-S-homo-CAP, and N,N'-dimethyl-4-S-CAP. We tested these five compounds in mice in vivo. After s.c. or i.p. injection of saline solution (in control groups) or one of the compounds, follicular melanocytes were examined by light and electron microscopy to assess the degree of melanocytotoxicity; N-Ac-4-S-CAP induced the most depigmentation (98%), whether given i.p. or s.c. After injection of 4-S-CAP or N-Ac-4-S-CAP, the number of murine B16F10 melanoma colonies formed in the lungs was determined; 4-S-CAP and N-Ac-4-S-CAP were almost equally effective, reducing the colonies to 32 and 25% of mean control, respectively. Metabolic studies of the urine showed 9% of 4-S-CAP and 20% of N-Ac-4-S-CAP injected i.p. were excreted unchanged in 24 h; 1.3% of the N-Ac-4-S-CAP was excreted as 4-S-CAP, indicating some conversion. We conclude that N-Ac-4-S-CAP is a suitable model for developing chemotherapy to treat melanoma characterized by high tyrosinase activity and melanin synthesis.

Animals↗
PubMed1990

Mechanism of growth inhibition of melanoma cells by 4-S-cysteaminylphenol and its analogues.

Our previous studies have shown that 4-S-cysteaminylphenol (4-S-CAP) causes a significant inhibition of in vivo melanoma growth and a marked depigmentation of black skin and hair follicles. These studies have suggested a role of tyrosinase in the manifestation of these in vivo effects. In this study 4-S-CAP and its analogues were examined for their effects on the growth of human melanoma cells in vitro. 4-S-CAP and 4-S-HomoCAP exhibited strong cytotoxicity with effects much greater than those of alpha-methyl-4-S-CAP and N,N-dimethyl-4-S-CAP. The cytotoxicity of the former two amines was completely prevented by semicarbazide, an inhibitor of plasma monoamine oxidase, while that of the latter two was not prevented by semicarbazide, catalase, and phenylthiourea, a tyrosinase inhibitor. In culture medium 4-S-CAP was rapidly converted by the action of monoamine oxidase present in fetal bovine serum to the aldehyde which was then metabolized to the alcohol and the carboxylic acid when cells were present. alpha-Methyl-4-S-CAP was found to exert higher cytotoxicity to cells with higher tyrosinase activity and melanin content. These results suggest that the in vitro cytotoxicity of 4-S-CAP and 4-S-HomoCAP is mediated through conversion to the aldehydes while that of alpha-methyl-4-S-CAP appears to be dependent on tyrosinase activity to some extent.

Antineoplastic Agents↗
PubMed1990

Complementary expression of melanosomal antigens and constant expression of pigment-independent antigen during the evolution of melanocytic tumours.

We have generated monoclonal antibodies (MoAbs) against melanosomal proteins (MoAb 1C11 and MoAb HMSA-1) and a cytoplasmic protein strongly synthesized in neoplastic melanocytes but not associated with melanogenesis (MoAb 7H11). An immunohistochemical study of paraffin sections showed that nearly 90% of epidermal neoplastic melanocytes, including melanomas, expressed 1C11 antigen, whereas this antigen was poorly preserved in dermal melanocytic cells except melanomas. HMSA-1 antigen was expressed in a complementary manner to 1C11 antigen, being found in dermal naevus cells but not generally in the epidermal regions, except for dysplastic naevi and melanomas. In contrast, 7H11 antigen was distributed in nearly 90% of melanocytic tumours except solar lentigo and lentigo maligna lesions. The failure of MoAb 1C11 to react with dermal melanocytes may reflect a subtle alteration in melanogenesis during tumour evolution. Overall, the combined use of MoAbs serves as an accurate diagnosis of melanocytic tumours, the pigment-independent MoAb 7H11 being particularly useful for amelanotic and metastatic lesions.

Antibodies, Monoclonal↗
PubMed1990

4-S-cysteaminylphenol and its analogues as substrates for tyrosinase and monoamine oxidase.

A phenolic amine compound, 4-S-cysteaminylphenol (4-S-CAP), was found to cause a selective destruction of follicular melanocytes. It was also recently found that 4-S-CAP can be a substrate for both tyrosinase and plasma monoamine oxidase (MAO). Both of these enzymes are capable of producing cytotoxic intermediates through their interaction with 4-S-CAP. To study the mechanism of selective melanocytotoxicity of phenolic amine compounds, we compared the in vivo depigmenting potency of 4-S-CAP and its three analogues; i.e., 4-S-HomoCAP, alpha-methyl(Me)-4-S-CAP and N,N-dimethyl(DiMe)-4-S-CAP, using black hair follicles. All four of these phenolic amine compounds possessed depigmenting potency. In this study we examined the kinetics of tyrosinase and MAO by these four compounds. 4-S-CAP and 4-S-HomoCAP were the substrates of both tyrosinase and MAO, whereas alpha-Me-4-S-CAP and N,N-DiMe-4-S-CAP were the substrates of tyrosinase alone. The rate of o-quinone formation by tyrosinase was not in parallel to the in vivo depigmenting potency of the tested compounds. It is therefore indicated that plasma MAO is not the enzyme directly responsible for the production of the melanocytotoxic intermediates from the phenolic amine compounds. We also found that the observed in vivo depigmentation results from complex processes involving the amount of o-quinone formed and the intracellular interaction of o-quinone with protein species.

Animals↗
PubMed1989

The synthesis of 4-S-cysteinyl-[U-14C]phenol, an experimental antimelanoma agent.

4-S-Cysteinylphenol (4-CP) has been shown to exert selective toxicity to melanocytes, causing growth inhibition of experimental malignant melanoma. 4-S-Cysteinyl-[U-14C]phenol (4-[U-14C]CP) has now been synthesized by reaction of [U-14C]phenol with excess L-cystine in HBr. After crystallization of unreacted cystine from the reaction mixture, 4-[U-14C]CP was recovered by HPLC in 57.6% radiochemical yield with a specific activity of 26.2 MBq mg-1 (15.2 mCi mmol-1). Radiochemical purity was greater than 99%. 2-S-Cysteinyl-[U-14C]phenol (2-[U-14C]CP), a side product with no antimelanoma activity, was recovered in 6% radiochemical yield.

Antineoplastic Agents↗
PubMed1989

Fine structural and immunohistochemical properties of dysplastic melanocytic nevi: comparison with malignant melanoma.

This study will review the clinical features of dysplastic melanocytic nevi (DMN) in Japanese cases, and then show the fine structure of melanosomes/melanogenesis in the dysplastic melanocytes and the immunohistochemical property of DMN as identified by monoclonal antibodies against human melanosome specific antigen (HMSA). The incidence of DMN is quite low in the Japanese. It is indicated that this fact may partly explain the low incidence of malignant melanoma in Japanese; in particular, low incidence in sun-exposed areas. The patients with DMN were largely males. They were different from ordinary Japanese in that they usually burn and tan poorly after sun exposure. In addition, the synthesis of melanosomes in the dysplastic melanocytes was found to be abnormal and characterized by a significant alteration in the fine structure of the melanosomal matrix and the pattern of melanization. These abnormal melanosomes reacted positively with MoAb HMSA-1 and HMSA-2, which identify the structural matrix protein of melanosomes unique to neoplastic melanocytes. Importantly, HMSA was present in both dysplastic melanocytes and melanoma cells, but not in epidermal melanocytes (nevus cells) of common melanocytic nevi.

Antigens, Neoplasm↗