Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of B16-F10 melanoma cells with dimethylsulfoxide (DMSO) or butyric acid (BA) inhibits cell growth and delays tumor appearance in syngeneic mice. Both agents induce morphological changes in these cells. Treatment of melanoma cells with DMSO results in a marked increase in tyrosinase activity and melanin content. BA, on the other hand, does not increase melanin content and decreases tyrosinase activity. The data show that there are marked differences in the effect of DMSO and BA on melanin biosynthesis, whereas both agents inhibit cell growth and cause a delay in tumor appearance. These findings indicate that decreased proliferation of melanoma cells and induction of melanin biosynthesis are not necessarily associated phenomena.
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PMID:Growth inhibition of murine melanoma by butyric acid and dimethylsulfoxide. 307 93

The B16/C3 murine melanoma is a pigmented tumor that is rich in the copper-containing enzyme, tyrosinase. This enzyme, which converts tyrosine to melanin precursors, is largely associated with membrane fractions of cells and exists in a number of discrete isozymic forms ranging in molecular mass from 58,000 to 150,000 daltons and pI from 3.4 to 5.2. One of these isozymes (Mr = 58,000, pI 3.4) has been purified to homogeneity. The purified enzyme catalyzes the hydroxylation of L-tyrosine to L-dihydroxyphenylalanine (L-DOPA) and the conversion of L-DOPA to dopaquinone. Ascorbic acid, tetrahydrofolate, and dopamine can serve as cofactors in the hydroxylase reaction. The Michaelis constants for the purified enzyme were 7 X 10(-4) M for L-tyrosine and 6 X 10(-4) M for L-DOPA. The Vmax for L-DOPA was much greater than the Vmax for L-tyrosine indicating that tyrosine hydroxylation is rate-limiting in melanin precursor biosynthesis. Two putative copper chelators, phenylthiourea and diethyldithiocarbamide inhibited both the tyrosine hydroxylase and L-DOPA oxidase activities of the enzyme. Phenylthiourea was a noncompetitive inhibitor while diethyldithiocarbamide was a competitive inhibitor indicating that these agents act by different mechanisms. When digested with proteases and glycosidases, higher molecular weight forms of tyrosinase co-migrated with the purified enzyme in isoelectric focusing and sodium dodecyl sulfate-polyacrylamide gel electrophoresis suggesting that the isozyme was derived from larger precursors. Thus, post-translational processing of tyrosinase may underlie isozyme diversity and this may be important in the control of melanogenesis in this tumor model.
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PMID:Tyrosinase isozyme heterogeneity in differentiating B16/C3 melanoma. 309 4

Phenotypic heterogeneity is a characteristic feature of tumor lesions in patients with melanoma. Variability can be observed in cell morphology, pigmentation, and antigen expression. To test whether phenotypic heterogeneity could be the result of events regulated during cell differentiation, we evaluated the expression of a panel of differentiation traits on melanoma cells. Metastatic melanoma lesions from two patients, designated FD and AP, were examined histologically and found to contain mixed populations of cells. Established melanoma cell lines derived from each of these lesions were subcloned at early passage in culture (passages 7 and 8) to create a panel of clones derived from each tumor. There was heterogeneity in the expression of differentiation-related traits in clones, corresponding to distinct phenotypes observed within the original tumors. Clones from patient FD corresponded to early to intermediate stages of melanocyte differentiation, and clones from patient AP ranged from intermediate to late stages. The influence of cholera toxin and PMA on differentiation of parental cultures and subclone was studied. Results of induction studies demonstrated a number of features of differentiation of melanoma cells: regulation of differentiation traits is coordinated as a program of traits expressed sequentially at specific stages; early traits, such as the epidermal growth factor receptor and the melanoma chondroitin sulfate proteoglycan antigen, are downregulated as melanoma cells differentiate, whereas late markers, including melanin, tyrosinase activity, and antigens expressed in mature melanosomes, are upregulated; Ia (class II major histocompatibility) antigens are characteristically expressed on melanomas corresponding to early or intermediate stages of differentiation and are regulated as part of the differentiation program; minimal changes in stage of differentiation were observed during induction of parental cultures with either cholera toxin or PMA, whereas definite shifts in differentiation could be induced in selected cloned subpopulations. We conclude that melanoma cells are not frozen at a specific stage of differentiation, but rather are capable of differentiating when exposed to appropriate signals. Diversity in the differentiation state of melanoma cells can account for much of the phenotypic heterogeneity observed in melanoma lesions.
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PMID:Phenotypic heterogeneity of melanoma. Relation to the differentiation program of melanoma cells. 310 78

A spontaneous, hypomelanotic variant (MI) of the highly melanotic transplantable hamster melanoma of Bomirski (Ma) is the subject of this report. Tyrosinase activity is 2-3 times higher, but melanin content significantly lower than in the parental Ma melanotic melanoma. Acid phosphatase activity is similar in both, but beta-glucuronidase and aryl-sulfatase A are 2-3 times higher in the hypomelanotic variant. Transplanted MI melanomas grow more slowly than the parental tumor, but metastasize with similar incidence and localization. Hypomelanotic variant melanoma cells, even those in grossly nonnecrotic parts of the transplants, show signs of low viability like swelling of the cytoplasm or cellular condensation, and disintegration. Autophagic vacuoles are numerous. They appear to be formed by enclosure of a portion of cytoplasm by cisternae of smooth endoplasmic reticulum or trans-Golgi network. These limiting cisternae contain tyrosinase as evidenced by deposition of electron dense reaction product on incubation with tyrosine or DOPA. Other sites of ultrastructural tyrosinase reaction are melanosomes and the smooth-surfaced cisternae and vesicles of the trans-Golgi network. We postulate the low cell viability, associated with autophagosome formation, is the cause for the growth retardation of the MI variant, and that the lower melanin content of these tyrosinase-rich cells is due to sequestration of a substantial portion of newly synthesized enzyme into autophagic vacuoles before it has the chance of being incorporated into melanosomes.
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PMID:Pathology and ultrastructural characteristics of a hypomelanotic variant of transplantable hamster melanoma with elevated tyrosinase activity. 311 4

Nuclear estrogen binding was characterized in HM-1, a malignant hamster melanoma cell line transplanted into male and female athymic mice following acute, subchronic, and chronic injection of estradiol. Nuclear binding was saturable, of high affinity (10(10) M-1) and readily soluble in low salt buffer. Saturation analyses revealed that [3H]estradiol in excess of 5.0 nM apparently bound to a second class of lower affinity (10(9) M-1), higher capacity cytosol sites. Enzyme-linked immunoassay with a specific monoclonal antibody (H222 Sp gamma) directed against the human estrogen receptor protein was in excellent agreement (r = 0.93) with values obtained using hydroxyapatite to separate bound from free ligand. Nuclear estrogen receptor content in HM-1 cells was increased maximally 1 h after acute s.c. injection of a low dose (0.1 microgram) of estradiol. The increase in nuclear receptor content was accompanied by an apparent rapid reduction in cytosol binding. Subchronic (3 days) and chronic exposure (35 days) to estradiol also produced a significant, dose-related increase in tumor nuclear estrogen receptor content. Cytosol binding for progestin was low (less than or equal to 2 fmol) to absent in HM-1 xenografts not exposed to estradiol. Subchronic and chronic exposure to estradiol induced a dose-related, specific, high affinity (10(9) M-1) cytosol binding protein for progestin(s) in HM-1 xenografts carried in male and female athymic mice. In contrast, progestin binding to nuclear receptor was not increased in estrogen-primed animals, nor did acute injection of progesterone (100 micrograms s.c.) increase the amount of saturable, high affinity (10(9) M-1) nuclear progestin receptor in control or estradiol-primed athymic mice. In contrast to the induction of progestin binding, tyrosinase activity was not altered by a similar exposure to estradiol when assayed at a saturating concentration of tyrosine. These observations suggest that the estrogen receptor in HM-1 cells may be functional but that pigmentary changes observed in mammals following chronic exposure to estradiol may not be mediated by a direct effect on the rate limiting enzyme of melanin synthesis.
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PMID:Effects of estradiol on estrogen receptor, progesterone receptor, and tyrosinase in hamster melanoma transplanted into athymic mice. 313 19

Meta-iodo-benzylguanidine (MIBG) is an analogue of the neurotransmitter norepinephrine. In its radioiodinated form, MIBG is clinically used as a tumor-targeted radiopharmaceutical in the diagnosis and treatment of adrenergic tumors. The potential cytotoxicity of the unlabeled drug was tested. MIBG appeared cytotoxic in a large panel of histogenetically different cell lines without preference against tumor cells of neural origin. The cytotoxicity of MIBG was higher than of the related mono-amine precursor, meta-iodo-benzylamine (MIBA). Drugs that block adrenergic receptors and inhibitors of tyrosinase or tyrosine hydroxylase had no effect on the cytostatic properties of MIBG. However, its activity was potentiated by the pharmacological inhibition of catecholamine degradation and by inhibitors of intracellular storage. MIBG had anti-tumor effects on L1210 leukemia and N1E115 neuroblastoma, grown as subcutaneous tumors in animals treated with MIBG in non-toxic schedules. The observations suggest that MIBG is cytotoxic in its native form and may contribute by this property to the clinical responses obtained with the radiolabeled drug at high concentrations.
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PMID:Cytotoxic and antitumor effects of the norepinephrine analogue meta-iodo-benzylguanidine (MIBG). 334 72

Because of the interest in possible links between defective differentiation and cellular malignancy, the effects were examined of induced cell differentiation upon the experimental metastatic potential of the sublines F1 and F10 of the B16 mouse melanoma. These cell lines normally have low and high rates, respectively, of colonization of the lungs of mice after i.v. injection. Cellular differentiation was assessed by pigmentation and tyrosinase activity. In both cell lines, low and high levels of differentiation could reproducibly be generated by culture, respectively, at a low extracellular pH and at a higher pH in the presence of a melanocyte-stimulating hormone. Surprisingly, in both lines the cells grown under conditions promoting differentiation showed a markedly higher rate of experimental metastasis, despite their slower proliferation in culture and in subcutaneous tumor implants, than the poorly differentiated cells. Radiolabeled well- and poorly pigmented cells were not initially deposited at significantly different rates in the lungs of mice after i.v. injection. However, subsequent retention in the lungs fell more quickly for the poorly differentiated cells. As indicated by tests in vitro, this difference appears not to be due to differential cytotoxicity by either host macrophages or natural killer cells, and it is under further study.
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PMID:Increased experimental metastatic capacity of a murine melanoma following induction of differentiation. 370 59

Continuous exposure for 96 hr of B16 melanoma cells in culture to 2.5 mM alpha-difluoromethylornithine (DFMO), a specific and irreversible inhibitor of ornithine decarboxylase, resulted in a marked increase in the activity of the enzyme tyrosinase, and also 20% cell kill as assessed by clonogenic assay. A 4-hr exposure to 0.4 mM 3,4-dihydroxybenzylamine (DHBA), a compound which is melanolytic due to its conversion to a cytotoxic quinone by the tumor specific enzyme tyrosinase, was found to be approximately equitoxic to 2.5 mM DMFO. However, a combination of DFMO (2.5 mM) and DHBA (0.4 mM) produced greater than 95% cell kill. This observed cytotoxicity with the combination suggests that induction of tyrosinase by DFMO sensitizes B16 melanoma cells to the melanolytic activity of DHBA. Oral administration of DFMO to mice bearing subcutaneous B16 melanomas also resulted in marked increases in the activity of tyrosinase in the tumor tissue. In mice inoculated intraperitoneally with 10(5) B16 melanoma cells, administration of DFMO via the drinking water (2%) increased the survival time by 8.5 days, whereas intraperitoneal administration of 300 mg/kg of DHBA for 14 days resulted in an increase in life span of 4.5 days compared to untreated controls. A combination of DFMO and DHBA prolonged the survival time by 14.6 days. These results indicate that DFMO in combination with an appropriate tyrosinase-dependent melanolytic agent might be useful in the chemotherapy of malignant melanomas.
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PMID:Potentiation by alpha-difluoromethylornithine of the activity of 3,4-dihydroxybenzylamine, a tyrosinase-dependent melanolytic agent, against B16 melanoma. 392 51

The objective of the present study was to investigate the effect of polyamine depletion by alpha-difluoromethylornithine (DFMO), a specific irreversible inhibitor of ornithine decarboxylase, on the growth and differentiation of B16 melanoma cells grown in culture and also as solid tumors in mice. Polyamine depletion by DFMO (2.5 mM) resulted in a complete inhibition of cell growth in culture and a 90% inhibition of viability of melanoma cells as determined by clonogenic assay at the end of 7 days after DFMO treatment. These results indicate that polyamine depletion induced by DFMO is cytotoxic to B16 melanoma cells in culture. Furthermore a 2- to 5-fold increase in tyrosinase activity and 10-fold accumulation of melanine were observed in polyamine depleted cells compared to control cultures. These effects of DFMO could easily be reversed by the addition of putrescine simultaneously with DFMO. Administration of different doses of DFMO in drinking water to B16 melanoma tumor bearing mice also resulted in an increase in tyrosinase activity and a dose dependent inhibition (86-90%) of tumor growth. Although one cannot rule out the possibility of induction of differentiated phenotype as a result of antiproliferative activity of DFMO, the data presented indicate that the unique sensitivity of melanoma to DFMO may be due to a combination of cell growth inhibition and concomitant induction of differentiation upon polyamine depletion. The results of the present study indicate that polyamines play an important role in growth and differentiation of melanoma and also provide an example of inhibition of tumor cell growth by induction of cellular differentiation.
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PMID:Effect of inhibition of polyamine biosynthesis by DL-alpha-difluoromethylornithine on the growth and melanogenesis of B16 melanoma in vitro and in vivo. 392 49

The present study was conducted to clarify the mechanism responsible for enhancement of the anti-melanoma activity of levodopa methylester by supplemental ascorbate in vivo. 5-Hydroxydopa, a known cytotoxic agent and the major metabolite formed from levodopa in the presence of ascorbate and mushroom tyrosinase in vitro, was assessed for its antitumor activity against i.p. and s.c. inoculated B16 melanoma, P388 leukemia, and L1210 leukemia in mice with and without supplemental ascorbate. Treatment with 5-hydroxydopa failed to significantly increase survival of mice bearing i.p. or s.c. pigmented and non-pigmented B16 melanomas even though it inhibited local tumor growth. Treatment increased survival of both P388 and L1210 leukemias, and this increase was more pronounced in mice bearing i.p. tumors than in mice bearing s.c. tumors. This treatment significantly decreased final tumor weight of both leukemias implanted s.c., and inhibited ascites formation in mice inoculated with i.p. tumors. Ascorbate supplementation decreased or abrogated the effect of 5-hydroxydopa on survival in mice bearing i.p. or s.c. leukemia tumors and decreased survival relative to control mice bearing i.p. or s.c. pigmented and s.c. non-pigmented tumors. It did not affect survival of treated mice bearing i.p. non-pigmented melanoma tumors. Ascorbate supplementation did not modify the effect of 5-hydroxydopa treatment on primary s.c. tumor growth in mice bearing melanoma or leukemia tumors nor did it affect ascites formation in treated mice bearing i.p. leukemia tumors. The lack of correlation between the observed inhibition of primary tumor growth and the absence of an effect on survival in 5-hydroxydopa treated mice bearing i.p. melanoma may relate to an inability of this drug to interfere with tumor metastasis. These data argue against a role for 5-hydroxydopa as a metabolically derived cytotoxic formed in situ during concurrent treatment with levodopa methylester and supplemental ascorbate.
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PMID:Influence of supplemental ascorbate on the antitumor activity of 5-hydroxydopa, a purported cytotoxic metabolite. 393 10


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