Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The uptake and binding of monoclonal antibodies (MAbs) in solid tumors after a bolus i.v. injection are described using a compartmental pharmacokinetic model. The model assumes that MAb permeates into tumor unidirectionally from plasma across capillaries and clears from tumor by interstitial fluid flow and that interstitial antibody-antigen interactions are characterized by the Langmuir isotherm for reversible, saturable binding. Typical values for plasma clearance and tumor capillary permeability of a MAb and for interstitial fluid flow and interstitial volume fraction of a solid tumor were used to simulate the uptake of MAbs at various values of the binding affinity or antigen density for a range of MAb doses. The model indicates that at low doses, an increase in binding affinity may lead to an increase in MAb uptake. On the other hand, at doses approaching saturation of antigen or when uptake is permeation limited, an increase in the binding affinity from moderate to high affinity will have only a small effect on increasing MAb uptake. The model also predicts that an increase in antigen density will greatly increase MAb uptake when uptake is not permeation limited. Our experiments on MAb uptake in melanoma tumors in athymic mice after injection of 20 micrograms MAb (initial plasma concentration, about 120 nM) are consistent with these model-based conclusions. Two MAbs differing in affinity by more than 2 orders of magnitude (3.8 x 10(8) M-1 and 5 x 10(10) M-1) but with similar in vivo antigen densities in M21 melanoma attained similar concentrations in the tumor. Two MAbs of similar affinity but having a 3-fold difference in in vivo antigen density in SK-MEL-2 melanoma showed that the MAb targeted to the more highly expressed antigen attained a higher MAb concentration. We also discuss the model predictions in relation to other experiments reported in the literature. The theoretical and experimental findings suggest that, for high dose applications, efforts to increase MAb uptake in a tumor should emphasize the identification of an abundantly expressed antigen on tumor cells more than the selection of a very high affinity MAb.
 ...
PMID:Predicted and observed effects of antibody affinity and antigen density on monoclonal antibody uptake in solid tumors. 172 9

In this report we have examined the ability of tumor necrosis factor-alpha (TNF) to induce the activity of phospholipase A2 (PLA2) in the cell line C3HA, a murine 3T3-like cell line which is normally resistant to TNF-induced cytolysis but can be sensitized with inhibitors of transcription and translation. Our results show that TNF is normally unable to induce the activity of PLA2 in this cell, as measured by the release of [3H]arachidonic acid. We find, however, that in the presence of either actinomycin D (Act D) or cycloheximide (CHI), TNF is indeed able to induce phospholipase activity and that the TNF-induced activation of PLA2 occurs 2-4 h before the onset of 51Cr release. The release of [3H]arachidonic acid was inhibited by 40-50% by pretreatment with 1 microM dexamethasone. Treatment with dexamethasone also inhibited cytolysis by 40-50% indicating that the CHI-dependent, TNF-induced activation of PLA2 is a cause, not an effect of cytolysis. The ability of TNF to induce the activity of PLA2 was also tested in two other cell types which are resistant to TNF except in the presence of Act D or CHI: SK-MEL-28, a human melanoma-derived cell line, and pVBETK-1cl15.2, an SV40-transformed murine L cell line. Our results were the same, treatment with a combination of Act D and TNF or CHI and TNF was required to cause activation of PLA2.
 ...
PMID:Inhibitors of transcription and translation act synergistically with tumor necrosis factor to cause the activation of phospholipase A2. 173 Jun 4

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.
 ...
PMID:Tyrosine transport in a human melanoma cell line as a basis for selective transport of cytotoxic analogues. 176 36

The MEL gene was identified following transfection of NIH3T3 mouse fibroblasts with DNA from a human melanoma cell line. The human MEL gene has been localized to 19cen-p13.2, a region in which translocation breakpoints occur in a number of malignancies. We have identified and sequenced human and mouse MEL cDNA clones which show homology of 92% and 96% at the nucleotide and amino acid levels respectively. The predicted human MEL protein shows only six amino acid differences between it and the recently described dog RAB8 protein. All of these changes occur in the 30 amino acids at the C-terminal of these proteins. MEL is similar to the RAB/YPT proteins in the region corresponding to the putative effector domain, suggesting that they may interact with the same cellular substrates. However, MEL contains a C-terminal CAAX motif in common with the majority of the RAS superfamily, unlike YPT1 and the majority of the RAB proteins.
 ...
PMID:The MEL gene: a new member of the RAB/YPT class of RAS-related genes. 188 11

The rap1/Krev-1 gene encodes a ras-related protein that suppresses transformation by ras oncogenes. We have purified an 88 kd GTPase activating protein (GAP), specific for the rap1/Krev-1 gene product, from bovine brain. Based on partial amino acid sequences obtained from this protein, a 3.3 kb cDNA was isolated from a human brain library. Expression of the cDNA in insect Sf9 cells resulted in high level production of an 85-95 kd rap1GAP that specifically stimulated the GTPase activity of p21rap1. The complete deduced amino acid sequence is not homologous to any known protein sequences, including GAPs specific for p21ras. Northern and Western blotting analysis indicate that rap1GAP is not ubiquitously expressed and appears most abundant in fetal tissues and certain tumor cell lines, particularly the Wilms' kidney tumor, SK-NEP-1, and the melanoma, SK-MEL-3, cell lines.
 ...
PMID:Molecular cloning of a GTPase activating protein specific for the Krev-1 protein p21rap1. 190 17

Preliminary evidence indicates that antitumor agents containing the o-dihydroxybenzene moiety exhibit enhanced antitumor activity toward malignant cells of high oxidative potential, such as melanoma cells. Based on this consideration, 11 hydroxybenzene acrylic acid derivatives of differing redox potential were prepared as potential substrates for the melanoma specific enzyme tyrosinase, that might exhibit general antitumor activity and enhanced cytotoxicity toward melanoma cells. Five of these compounds [alpha-cyano-beta-(4-hydroxyphenyl)-, alpha-cyano-beta-(3,4-dihydroxyphenyl)-, and alpha-cyano-beta-(3,4,5-trihydroxyphenyl)acrylic acid (THPPA), and 3,4-dihydroxy- and 3,4,5-trihydroxybenzalcyanoacetamide] were found to be substrates for tyrosinase with Km values from 0.08 to 4.13 mM and Vmax values from 0.18 to 3.02. These data indicate that as the number of hydroxy groups increases, the rate of oxidation increases, and that cyanoamides were faster reacting than corresponding cyanoacids, with dicyanides the least reactive. In contrast, cyanoamides were less effective as substrates than cyanoacids. In vitro studies showed all but two compounds were active against L1210 (IC50 range 21-980 microM), SK-MEL-28 (IC50 range 54-950 microM), and SK-MEL-30-3 (IC50 range 54-190 microM). Only THPPA was active in vivo against L1210 and B-16 melanoma.
 ...
PMID:Polyhydroxylated phenylacrylic acid derivatives as new anti-tumor agents. 190 1

Human peripheral blood lymphocytes (PBL) from 10 healthy donors were in vitro immunized using the human melanoma cell line SK-MEL 28 as an immunogen. The parameters necessary to obtain an optimal immune response against the tumor cells in vitro were determined. Different ratios of PBL and SK-MEL 28 were tested during the in vitro immunization period, and their effect on cell viability, specific antibody secretion, and yield of antigen-specific EBV clones was determined. A statistically significant positive dose-response relation was shown to exist between the immunogenic dose present during in vitro immunization and the number of antigen-specific EBV clones that was obtained. A ratio of PBL:SK-MEL 28 cells of 1:1 was found to be optimal and gave 2.6% positive clones from which human monoclonal antibodies specific for the melanoma cells were detected.
 ...
PMID:In vitro immunization of human B lymphocytes with cultured melanoma cells (SK-MEL 28). 196 73

To study the induction of differentiation in human melanoma cells, we treated 12 melanoma cell lines with mycophenolic acid and tiazofurin, inhibitors of IMP dehydrogenase (IMPDH). In all cell lines studied, both agents inhibited cell growth and increased melanin content. However, the degree of growth inhibition did not necessarily correspond to the increase in melanin content. A detailed analysis of the HO and SK-MEL-131 cell lines indicated that mycophenolic acid and tiazofurin caused a time- and dose-dependent increase in the expression of a series of other maturation markers, including formation of dendrite-like structures, tyrosinase activity, and reactivity with the CF21 monoclonal antibody. The growth inhibition and melanogenesis induced by the IMPDH inhibitors was abrogated by the addition of exogenous guanosine. No such effect was observed after treatment of the cells with phorbol 12-myristate 13-acetate or retinoic acid, two other inducers of differentiation in these cells. The mycophenolic acid- and tiazofurin-treated cells also showed an increased level of IMPDH mRNA and protein, perhaps because of compensation for the inhibitor-mediated decrease in IMPDH activity. In contrast, treatment with phorbol 12-myristate 13-acetate or retinoic acid resulted in decreased levels of IMPDH mRNA and protein. The lack of a consistent pattern of IMPDH expression in the cells treated with IMPDH inhibitors and phorbol 12-myristate 13-acetate or retinoic acid suggests that the altered expression of IMPDH is not a general requirement for the induction of cell differentiation in these cells. Our results also suggest that IMPDH inhibitors may provide a useful approach to circumvent the differentiation block in melanoma.
 ...
PMID:Induction of cell differentiation in melanoma cells by inhibitors of IMP dehydrogenase: altered patterns of IMP dehydrogenase expression and activity. 198 May 99

Through the extensive investigation of new mitomycin C (MMC) derivatives, several compounds with disulfide at N-7 were found to show activities superior to MMC against murine Sarcoma 180 solid tumor. Among them, 7-N-[[2-[[2-(gamma-L-glutamylamino)ethyl]dithio]ethyl]]- mitomycin C (KW-2149) was selected for further evaluation of antitumor activity and toxicity in mice. KW-2149 exhibited activity superior to MMC in increasing survival of i.p. inoculated P388 leukemia-, M5076 sarcoma-, and B16 melanoma-bearing mice. KW-2149 administered i.v. also exhibited superior activity in inhibiting the growth of s.c. inoculated P388 leukemia, M5076 sarcoma, and colon 26 adenocarcinoma and in increasing survival of i.v. inoculated P388 leukemia- and M5076 sarcoma-bearing mice. Furthermore, KW-2149 remarkably increased the life span of MMC-resistant P388 leukemia- and L1210 leukemia-bearing mice. KW-2149 and MMC inhibited the growth of human tumors inoculated into nude mice. The activity of KW-2149 was prominent in human lung carcinoma Lu-65 and Lu-99, bladder carcinoma T24, and epidermoid carcinoma A431. KW-2149 was comparable to MMC in decreasing the number of WBC in the peripheral blood, and the thrombopenia induced by KW-2149 was mild and recovery was rapid. The in vitro anticellular spectrum of KW-2149 against 23 human tumor cell lines was similar to that of MMC. However, KW-2149 inhibited the growth of the cell lines at concentrations of 10- to 100-fold lower than MMC and showed efficient cytotoxicity against MMC-insensitive tumor cell lines. These included lung epidermoid carcinoma Calu-1, stomach carcinoma MKN-28, colon adenocarcinoma DLD-1, colon adenocarcinoma LoVo, bladder carcinoma HT-1197, sarcoma G-292, and melanoma SK-MEL-28 cells. These results indicate that KW-2149 bears interesting characteristics as a new anticancer drug and warrants further development.
 ...
PMID:Antitumor activity of 7-N-[[2-[[2-(gamma-L-glutamylamino)ethyl]dithio]ethyl]]-mitomycin C. 198 76

The role of the transferrin homologue, melanotransferrin (p97), in iron metabolism has been studied using the human melanoma cell line, SK-MEL-28, which expresses this antigen in high concentrations. The release of iron and transferrin were studied after prelabelling cells with human transferrin doubly labelled with iron-59 and iodine-125. Approx. 45% of internalised iron was in ferritin with little redistribution during reincubation. Iron release was linear with time, while transferrin release was biphasic, suggesting that iron was leaving the cell independently of transferrin. Unlabelled diferric transferrin increased transferrin release, implying a degree of coupling between cell surface binding, internalisation and release of transferrin. Increasing the preincubation time increased the amount of transferrin which remained internalised within the cell. A membrane-bound, iron-binding component with properties consistent with melanotransferrin was observed. Desferrioxamine or pyridoxal isonicotinoyl hydrazone could not remove iron from this compartment, suggesting a high affinity for iron. The number of membrane iron-binding molecules per cell was estimated to be 387,000 +/- 7000 . The non-transferrin-bound membrane Fe did not decrease during reincubation periods up to 5 h, suggesting that the cell was not utilising it. Hence, melanotransferrin may not have a role in internalising iron in melanoma cells.
 ...
PMID:The release of iron and transferrin from the human melanoma cell. 200 12


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>