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

Recent evidence suggests a role for sigma (sigma) binding sites in maintenance of cell growth and/or proliferation. The present study examines, for the first time, the effect of sigma binding site ligands on in vitro growth of tumour cells derived from human mammary adenocarcinoma (MCF-7, MDA) and colon carcinoma (LIM 1215, WIDr), and melanoma (Chinnery). Addition of the sigma ligands haloperidol, reduced haloperidol, 1,3-di(2-tolyl)guanidine (DTG), (+)- and (-)-N-allylnormetazocine (SKF 10,047), (+)- and (-)-pentazocine and rimcazole at 6.25, 12.5, 25, 50, 100 microM at the beginning of culture or 24 h later, inhibited cell proliferation in a dose-dependent manner. Light microscopy revealed cell detachment, rounding and cell death. The potency of sigma ligands on melanoma cells was rimcazole > reduced haloperidol > haloperidol = (+)-pentazocine, whereas DTG and (+)- and (-)-SKF 10,047 and (-)-pentazocine had no effect even at 100 microM. In contrast, in MCF-7 cells, rimcazole > reduced haloperidol > haloperidol > (-)-pentazocine > DTG > (+)-pentazocine > (+)-SKF 10,047 > (-)-SKF 10,047. For colon cancer cells, reduced haloperidol > DTG > haloperidol = (-)-pentazocine = (+)-pentazocine = (+)-SKF 10,047. Of all the ligands tested, rimcazole and reduced haloperidol were the most potent inhibitors of cell proliferation. With the exception of one slow-growing colon cancer cell line (LIM 1215), the order of sensitivity of various cell lines to reduced haloperidol, SFK 10,047, DTG, haloperidol and (+)- and (-)-pentazocine was colon carcinoma > mammary adenocarcinoma > melanoma, whereas to rimcazole, the sensitivities of mammary adenocarcinoma and melanoma cells were comparable. The effect of sigma ligands in MCF-7 and melanoma cells was not due to blockade of dopamine D1 and D2 receptors, serotonin (5-HT2) receptors, N-methyl-D-aspartate (NMDA)/phencyclidine receptors, beta-adrenoceptors or opioid receptors, since 100 microM SCH 23390, raclopride, mianserin, (+)-MK-801, propranolol and 1 microM naloxone respectively, were ineffective. However, mianserin and raclopride were inhibitory to melanoma cells and one colon carcinoma cell line, respectively. Taken together, the results are consistent with the recent observation that sigma binding sites may play a role in cell growth and/or cell proliferation.
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PMID:Sigma binding site ligands inhibit cell proliferation in mammary and colon carcinoma cell lines and melanoma cells in culture. 767 99

Using an in situ kinase assay we have identified kinases that are elevated in some multidrug resistant cells. Kinases were detected by measurement of 32P incorporation in proteins that were renatured after being subjected to SDS-polyacrylamide gel electrophoresis and transferred to polyvinylidene difluoride membranes [Ferrell and Martin: J Biol Chem 264:20723-20729, 1989; Mol Cell Biol 10:3020-3026, 1990]. Kinases at 79, 84, and 92 kDa showed increased activity in the multidrug resistant human KB-V1 cells as compared to the sensitive parental KB-3-1 cells. The KB-V1 multidrug resistant cell line exhibited a 170 kDa membrane associated kinase activity that was not present in the parental drug sensitive line. The 170 kDa kinase activity was not affected by Ca++, phosphatidylserine, or cAMP, but was diminished after incubation in the presence of the kinase inhibitors staurosporine, K252a and KT5720. The 170 kDa kinase activity phosphorylated mainly threonine, with no evidence of tyrosine phosphorylation, and was not identical to either the multidrug resistance associated P-glycoprotein or the EGF receptor. Other multidrug resistant cell lines also showed elevated 170 kDa kinase activity, such as the human breast cancer MCF-7/Adr(R) and murine melanoma B16/Adr(R) cells, but the activity was not present in murine leukemia P-388 sensitive or multidrug resistant cells.
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PMID:Identification of a 170 kDa membrane kinase with increased activity in KB-V1 multidrug resistant cells. 769 26

Effects of 1,15-bis(ethylamino)-4,8,12-triazapentadecane (BE3333), the least toxic bis(ethyl)pentaamine, on the growth of tumor cells were studied in in vitro systems and with tumor xenografts in mice. BE3333 suppressed ornithine decarboxylase and S-adenosylmethionine decarboxylase, induced spermidine/spermine N1-acetyltransferase, and thus decreased the amount of polyamines. BE3333 accumulated in cells at a concentration 3-5-fold that of spermine in control cells through the polyamine transport system. The accumulated BE3333 inhibited protein synthesis, especially mitochondrial protein synthesis, and decreased the amount of ATP. The inhibition of protein synthesis was correlated with the subsequent inhibition of cell growth. BE3333 showed inhibitory effects in in vitro systems against the growth of mouse FM3A mammary carcinoma cells, human SW480 and SW620 colon tumor cells, Lu-65A and A549 lung tumor cells, MCF-7 breast tumor cells, and MALME-3M and A375 melanoma cells at a range of 0.5-10 microM. Intravenous (30 mg/kg) or i.p. (50 mg/kg) daily injections of BE3333 for 5 or 7 days greatly suppressed the growth of human colon tumor SW620 xenotransplanted into nude mice. Similar antitumor activity was obtained with continuous infusion of BE3333 into the peritoneal cavity (80 mg/kg), but not with p.o. administration (200 mg/kg). BE3333 also showed inhibitory effects against the growth of lung tumors (Lu-65, Lx-1, Lc-1, and Lu-61), stomach tumors (Sc-6 and St-15), and melanoma (SEKI) xenotransplanted into nude mice. The results indicate that BE3333 is effective against both rapid- and slow-growing tumors, with reasonable short-term host toxicity.
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PMID:Inhibition of the growth of various human and mouse tumor cells by 1,15-bis(ethylamino)-4,8,12-triazapentadecane. 778 Sep 77

Thirteen tumor-derived cell lines of human and nonhuman origin and from various tissues were examined for the presence and density of sigma-1 and sigma-2 receptors. Sigma-1 receptors of a crude membrane fraction were labeled using [3H](+)-pentazocine, and sigma-2 receptors were labeled with [3H]1,3-di-o-tolylguanidine ([3H]DTG); in the presence or absence of dextrallorphan. [3H](+)-Pentazocine-binding sites were heterogeneous. In rodent cell lines (e.g., C6 glioma, N1E-115 neuroblastoma, and NG108-15 neuroblastoma x glioma hybrid), human T47D breast ductal carcinoma, human NCI-H727 lung carcinoid, and human A375 melanoma, [3H](+)-pentazocine bound to high- and low-affinity sites with Kd1 = 0.67-7.0 nM, Bmax1 = 25.5-108 fmol/mg protein, Kd2 = 127-600 nM, and Bmax2 = 942-5431 fmol/mg protein. However, [3H](+)-pentazocine bound to a single site in other cell lines. In human U-138MG glioblastoma, SK-N-SH neuroblastoma, and LNCaP.FGC prostate, Kd = 28-61 nM and Bmax = 975-1196 fmol/mg protein, whereas in ThP-1 leukemia Kd = 146 nM and Bmax = 1411 fmol/mg protein. The sigma-1-like nature of [3H](+)-pentazocine-binding sites was confirmed by competition studies which revealed high affinity for haloperidol and enantioselectivity for (+)-pentazocine over (-)-pentazocine. Interestingly, human MCF-7 breast adenocarcinoma showed little or no specific binding of [3H](+)-pentazocine, suggesting the absence of sigma-1 receptors in this cell line. All cell lines examined expressed a high density of sigma-2 receptors with Kd values for [3H]DTG ranging from 20 to 101 nM and Bmax values of 491 to 7324 fmol/mg protein. Competition studies indicated possible heterogeneity of sigma-2 receptors. While sites labeled by [3H]DTG in all cell lines tested exhibited affinity for haloperidol and preference for (-)-pentazocine over the (+)-enantiomer, human cell lines generally showed 4- to 7-fold lower affinity for haloperidol and approximately 10-fold lower affinity for (-)-pentazocine compared with the rodent cell lines. The high density of sigma-1 and sigma 2-binding sites in these cell lines suggests important cellular functions in cancer, as well as potential diagnostic utility for tumor-imaging agents which target sigma sites. These cell lines may be useful as model systems in which to study the functions of sigma sites in normal tissues, as well as their possible role in tumor biology.
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PMID:Sigma-1 and sigma-2 receptors are expressed in a wide variety of human and rodent tumor cell lines. 781 73

Gossypol is a lipid soluble polyphenolic compound isolated from cotton seed oil which has been previously shown to have antiproliferative activity in vitro against a variety of human solid tumor cell lines. It has been extensively tested in clinical trials as a male contraceptive agent and found to be well tolerated. Its mechanism of action is thought to be inhibition of cellular energy metabolism. It inhibits glycolysis through inhibition of LDH isoenzyme type 5, and it inhibits mitochondrial oxidative phosphorylation and electron transport. We tested the in vitro antiproliferative effect of gossypol against four well characterized human glioma cell lines, HS 683, U373, U87 and U138, and one rat glioma cell line, C6, using the colorimetric Microculture Tetrazolium Assay (MTT). Cytotoxicity was found to be concentration and time dependent and increased with incubation times up to 8 days. The relative sensitivity of the glioma cell lines to gossypol at 48 hour incubation correlated with their respective LDH isoenzyme profiles, with the more sensitive cell lines expressing increased cathodal LDH isoenzymes (LDH5). The in vitro cytotoxicity of gossypol to these CNS tumor lines was compared to the other non central nervous system solid tumor cell lines which had been previously reported as being sensitive to gossypol, including SW-13 (adrenal), MCF-7 (breast), T47-D (breast), and HeLa (cervical). Additional lines tested included SK-MEL-3 (melanoma), Colo 201 (colon) and BRW, a line established in our laboratory from a patient with a Primitive Neuroectodermal tumor. C6, HS 683, and BRW had similar IC50s as the sensitive solid tumor cell lines. U373, U87 and U138 had significantly less sensitivity at 48 hours. There was greater cytotoxicity and no significant differences in the IC50s between any of cell lines at 8 day incubations. Additionally, we tested the cytotoxicity of gossypol against BRW in vivo, using the nude mouse xenograft model. Gossypol, given at a dose of 30 mg/kg per day five days a week for four weeks orally via gavage, was found to decrease the mean tumor weight of treated xenografts by more than 50% as compared to untreated xenografts. These findings suggest that gossypol has potential for further study as an agent for the treatment of primary CNS malignancies.
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PMID:In vitro and in vivo cytotoxicity of gossypol against central nervous system tumor cell lines. 781 2

FC-2.15 is an IgM monoclonal antibody (MAb) obtained by immunizing Balb/c mice with tumor epithelial cells from a human undifferentiated primary breast carcinoma. FC-2.15 reacts with 93.9% (31/33) of human breast primary tumors, independently of their histology and hormone receptor content. Moreover, FC-2.15 reacts with 79.6 +/- 13.8% (mean +/- SD) of total breast malignant tumor cells and with 88.7 +/- 9.9% of proliferating tumor cells. It recognizes other neoplasia such as colon cancer, squamous carcinoma and melanoma. Among the normal tissues examined, strong cross-reactivity was found with kidney proximal convolute tubules, bone marrow myeloid progeny, peripheral granulocytes and large bowel epithelium. Through Western blots, FC-2.15 recognizes three major bands of Mr 160 kDa, 130 kDa and 115 kDa in membrane extracts of MCF-7 cells grown in nude mice and of human breast carcinoma and three major bands of 250 kDa, 185 kDa and 105 kDa in membrane extracts of peripheral granulocytes. This MAb mediates complement- cytotoxicity against malignant cells, reducing the clonogenic capacity of breast primary tumor cells and MCF-7 cells to 35.6 +/- 41.2% and 11.7 +/- 4.8% of control values respectively, whereas that of normal bone marrow cells is not affected (104.7 +/- 17.4%).
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PMID:Description of a new monoclonal antibody, FC-2.15, reactive with human breast cancer and other human neoplasias. 782 91

The intracellular distribution of the anthracyclinic antibiotic adriamycin in living cultured cells has been investigated by confocal microscopy. In human melanoma cells (M14), adriamycin was localized inside the nuclei. When adriamycin-treated M14 cells were allowed to recover in drug-free medium, a complete efflux of the drug from the nucleus was revealed. In recovered cells, a weakly fluorescent signal was observed in the perinuclear region. When M14 cells were recovered in a medium containing colcemid, a microtubule depolymerizing agent, the drug transport from the nucleus to the cell periphery appeared to be inhibited, suggesting that the microtubule network is strongly involved in drug transport mechanisms. In multidrug-resistant (MDR) cells the intracellular location of adriamycin was shown to be noticeably different from that of the parental wild-type cells. In particular, in resistant human breast carcinoma cells (MCF-7), adriamycin appeared to be exclusively located within the cytoplasm whereas the nuclei were shown to be completely negative. When adriamycin treatment was performed in association with MDR revertants, such as Lonidamine (inhibitor of the energy metabolism) or verapamil (inhibitor of the P-glycoprotein efflux pump), a marked enhancement of the cytoplasmic signal was observed in resistant cells. Under these conditions, adriamycin appeared concentrated in the perinuclear region, but the nuclei were still negative. Confocal microscopy proved to be a very useful method for the study of the intracellular transport of fluorescent substances, such as anthracyclinic antibiotics, and for the investigation of the multidrug resistance phenomenon in tumour cells.
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PMID:Intracellular localization of the antitumour drug adriamycin in living cultured cells: a confocal microscopy study. 786 63

1,25-(OH)2-Vitamin D3, the active metabolite of vitamin D, is a secosteroid hormone with known differentiating activity in leukemic cells. Studies have demonstrated the presence of vitamin D receptors (VDR) in a wide range of tissues and cell types. Antiproliferative activity of 1,25-(OH)2-vitamin D3 has been documented in osteosarcoma, melanoma, colon carcinoma, and breast carcinoma cells. This study was designed to analyze vitamin D receptor level in breast cancer cells as a marker of differentiation and as a predictor of growth inhibition by 1,25-(OH)2-vitamin D3. VDR messenger RNA was found to be present in relatively high levels in well-differentiated cells and in low levels in poorly differentiated cells. All cell lines had detectable VDR mRNA. Radiolabeled ligand binding assay showed a similar pattern. MCF-7 and T47D cells, which express VDR at moderate levels, showed significant growth inhibition by 10(-9) M1,25-(OH)2-vitamin D3 (p < 0.05). MDA-MB-231 cells, which have very low levels of VDR, demonstrated no growth inhibition by 1,25-(OH)2-vitamin D3 at concentrations up to 10(-6) M. Based on these results it can be stated that VDR expression is lost with de-differentiation and that receptor is essential for the antiproliferative response to 1,25-(OH)2-vitamin D3.
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PMID:Vitamin D receptors in breast cancer cells. 788 Oct 99

Frozen sections of 52 human solid tumours (38 malignant and 14 benign) of varied histogenesis were immunohistochemically stained with well characterised monoclonal antibodies (MAbs) to human interleukin 2 (IL-2) and the alpha and beta chains of its receptor (R). In all malignant specimens, the tumour cells expressed the IL-2R beta subunit (p75) but not the IL-2R alpha subunit (CD25). In 36 of 38 malignant tumours examined, there was conspicuous staining for IL-2 in the tumour cell nuclei/nucleoli and perinuclear cytoplasm. In the human solid tumour cell lines G361 (melanoma), A549 (lung), MCF-7 (breast) and WiDR (colorectal), both subunits of the IL-2R appeared to be expressed, although the alpha subunit only weakly. Exogenous addition of human recombinant (r) interleukin 2 altered cell numbers in 3 of the 4 cell lines (WiDR was refractory). When grown in the absence of exogenously added rIL-2, IL-2 staining was observed in all cell lines. The pattern of distribution was similar to that exhibited by the tumour cells in situ (i.e., a nuclear/nucleolar localisation). In G361 melanoma cells, this IL-2 staining was present in proliferating cells but disappeared as the cultures approached confluence. Addition of an IL-2R beta subunit blocking antibody to growing G361 cultures (grown in the absence of rIL-2) resulted in a significant reduction in cell numbers. We propose, therefore, that the presence of immunoreactive IL-2 and IL-2R expression is characteristic of human malignant cells and that IL-2 may play a role in the autocrine stimulation of proliferation of malignant cells, such as G361 melanoma cells.
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PMID:Interleukin 2 receptor expression and interleukin 2 localisation in human solid tumor cells in situ and in vitro: evidence for a direct role in the regulation of tumour cell proliferation. 789 42

Lymphokine Activated Killer (LAK) cells, stimulated by interleukin 2 (IL-2) have a pronounced antitumor effect in the therapy of melanoma and renal cancers. LAK cells were cultivated in presence of the nodules of the human breast adenocarcinoma cell line MCF-7 maintained in organotypic culture to study the interactions between lymphocytes and breast tumor cells. After two days of co-culture, the proliferation of MCF-7 nodules and that of LAK cells was diminished about five folds. The cytotoxic effect of the latter, appreciated by Chrome 51 release was unchanged after the coculture. In histological sections, the penetration of the LAK cells into the MCF-7 nodules was accompanied by an increase of tumor necrosis but also by a glandular differentiation of cancerous tissue. Polarized epithelial cell formations bording neoplasic lumens with intracytoplasmic vacuoles filled with mucus, appeared in the nodules. The immunohistochemistry underlines the presence of T lymphocytes marked by UCHL1 and CD3 antibodies and of Natural Killer (NK) cells marked by IOT10, located between the MCF-7 cancer cells. In electron microscopy, the membrane contacts were tight and were accompanied by the appearance of secondary lysosomes and nuclear alterations. The relatively low infiltration level of the nodules may lead to the supposition that an indirect mechanism will intervene in this dual action of a LAK cells: increase of necrosis, although partially, and development of glandular and functional differentiation.
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PMID:[Effects of LAK cells activated by IL-2 on MCF-7 human breast cancer cell line maintained in organotypic culture]. 820 46


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