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)

Cell lines resistant to five antitumor alkylating agents (CDDP, PAM, 4-HC, HN2, and BCNU) were developed from five parental human tumor lines representative of solid tumors with a range of sensitivities to antitumor alkylating agents. The parental cell lines were SCC-25 squamous carcinoma of the head and neck, MCF-7 breast carcinoma, SW2 small-cell lung cancer, SL6 non-small-cell lung carcinoma, and G3361 melanoma. Survival curves using colony formation as the endpoint were generated for each of the 25 cell lines to each of the five alkylating agents. Comparison of the drug concentrations that reduced the survival of the alkylating agent-resistant cell lines by 90% (IC90 values) with the IC90 values obtained for the corresponding parental cell lines was used as a measure of the resistance/sensitivity of the alkylating agent-resistant lines to each drug tested. Although cross-resistance among the alkylating agents was generally uncommon, several patterns of response emerged. Cross-resistance occurred in 27 of the 105 determinations and occurred most frequently in the cell lines in which resistance was developed to PAM (57%) or BCNU (38%). Cross-resistance to HN2 occurred most frequently. Collateral sensitivity was equally as common, occurring in 25 of the 105 determinations. Collateral sensitivity occurred most frequently in the cell lines made resistant to 4-HC. The 4-HC-resistant cell lines were most frequently collaterally sensitive to PAM and to BCNU. Cross-resistance developed most frequently in the MCF-7 breast carcinoma and SCC-25 squamous-cell carcinoma cell lines, whereas collateral sensitivity developed most frequently in the SW2 small-cell lung cancer line and the G3361 melanoma cell line and least frequently in the MCF-7 breast carcinoma cell line and the SL6 non-small-cell lung cancer cell line. The implication of these findings for the development of strategies for clinical treatment are discussed.
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PMID:Antitumor alkylating agents: in vitro cross-resistance and collateral sensitivity studies. 826 70

We previously found that transferrin (Tf) differentially stimulated the growth of highly metastatic variant lines of murine melanoma and that these highly metastatic cells also had greater numbers of Tf receptors on their cell surfaces. In the present study we found that highly metastatic rat mammary adenocarcinoma cell lines also responded differentially to Tf in proliferation assays, and cell monolayers bound Tf in relation to their metastatic potential (MTPaB10 > MTPaB5 > MTLn3 > MTLn2 > MTC > MTF7 > MTPa). The brain-colonizing lines PaB10 and PaB5 were the most responsive to Tf and had the highest numbers of Tf receptors. Different human breast cancer cell lines also responded differentially to Tf in proliferation assays and bound different amounts of Tf to their cell surface Tf receptors. Transferrin binding, but not growth response, correlated with metastatic and invasive properties of lines selected from the human MCF-7 series (MCF7/LCC2 > MCF7/LCC1 > MCF7). In examining the transferrin binding and growth response of lines from the human MDA series, the Tf binding and growth response was MDA231 > MDA435 > MDA468. The lines MDA435 and MDA231 were metastatic in nude mouse assays, whereas the line MDA468 was not. Scatchard analysis indicated the presence of a single class of receptor for Tf on the rat and human mammary cell lines. The results suggest that neoplastic cells displaying various metastatic properties may express differing numbers of Tf receptors and respond differently to growth factors such as Tf.
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PMID:Differences in transferrin response and numbers of transferrin receptors in rat and human mammary carcinoma lines of different metastatic potentials. 831 58

Isoenzymes of 3',5'-cyclic nucleotide phosphodiesterase (PDE) have been characterized in B16 murine melanoma cells and MCF-7 human mammary carcinoma cells. Separation of soluble phosphodiesterase activity by fast protein liquid chromatography on a Mono-Q column resolved three isoenzymes, MCF-7 cells contained a cyclic GMP-specific isoenzyme (PDE-V), a cyclic GMP-activable isoenzyme (PDE-II), and a cyclic AMP-specific isoenzyme (PDE-IV). B16 cells contained a cyclic GMP-specific isoenzyme (PDE-V), a Ca2+/calmodulin-activated isoenzyme (PDE-I), and a cyclic AMP-specific isoenzyme (PDE-IV). A series of PDE inhibitors was tested for their activity spectrum on PDE isoenzymes. Inhibition of PDE activity in B16 cells by the new compound DC-TA-46, was found to result specifically from PDE-IV inhibition [50% inhibition (IC50) = 0.03 microM]. Much lower inhibitory activity was observed for DC-TA-46 toward PDE-I (IC50 = 5 microM) and PDE-V (IC50 = 14 microM). DC-TA-46 was found to inhibit growth of B16 melanoma and MCF-7 mammary carcinoma cells dose dependently (B16: IC50 = 1.7 microM, MCF-7: IC50 = 2 microM). At 2 microM concentration, growth inhibition of B16 melanoma cells was 60%, concomitant with a decrease in PDE activity of 63% and an increase in cAMP level of 59%. In contrast, incubation with inhibitors specific for PDE-I and PDE-V resulted only in marginal or undetectable growth inhibition. The results suggest a correlation between PDE-IV inhibition and growth inhibition. PDE-IV thus appears to be a potential new target for antiproliferative treatment.
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PMID:3',5'-Cyclic nucleotide phosphodiesterase in tumor cells as potential target for tumor growth inhibition. 839 85

Previous studies have documented differential sensitivity of human lung cancer and melanoma cell lines to the cytotoxic effects of N1, N12-bis(ethyl)spermine (BESpm). We show here that BESpm can significantly inhibit the growth of six human breast cancer cell lines with 50% inhibitory concentration in the microM range. The degree of inhibition does not correlate with estrogen receptor status. Detailed studies with estrogen receptor-positive MCF-7 and estrogen receptor- negative Hs578t cells show a similar dose-response curve with concentrations of 1-10 microM resulting in maximal growth inhibition. Growth inhibition in both lines is associated with an 8-12-fold induction of the polyamine catabolic enzyme, spermidine/spermine N1-acetyltransferase, and a progressive decrease in intracellular polyamine levels over 6 days even though steady-state levels of BESpm are achieved within 24 h. Similar studies on WTMCF7 and AdrRMCF7 cells show that the acquisition of resistance to hormonal or doxorubicin therapy is not associated with resistance to the growth-inhibitory effects of BESpm. These results suggest that BESpm exerts similar growth-inhibitory effects against both hormone-responsive and -unresponsive human breast cancer cells, a finding which has significance for the potential use of polyamine analogues in treating human breast cancer.
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PMID:Growth inhibition of hormone-responsive and -resistant human breast cancer cells in culture by N1, N12-bis(ethyl)spermine. 848 9

MKT-077 (formerly known as FJ-776) is a newly synthesized, highly water-soluble ( > 200 mg/ml) rhodacyanine dye that exhibits significant antitumor activity in a variety of model systems. In culture, MKT-077 inhibits the growth of five human cancer cell lines (colon carcinoma CX-1, breast carcinoma MCF-7, pancreatic carcinoma (CRL 1420, bladder transitional cell carcinoma EJ, and melanoma LOX) but not monkey kidney CV-1, an indicator cell line for normal epithelial cells. In nude mice, MKT-077 inhibits the growth of s.c. implanted human renal carcinoma A498 and human prostate carcinoma DU145 and prolongs the survival of mice bearing i.p. implanted human melanoma LOX (tumor:control = 344%). Subcellular localization indicates that MKT-077 is taken up and retained by mitochondria, and flow cytometric analysis suggests that CX-1 cells take up MKT-077 to a much greater extent than CV-1 cells. Quantitation of MKT-077 uptake by ethanol extraction shows that CX-1 cells accumulate 65-fold more MKT-077 than do CV-1 cells. MKT-077 is the first delocalized lipophilic cation with a favorable pharmacological and toxicological profile in preclinical studies. MKT-077 is now being investigated in Phase I clinical trials.
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PMID:MKT-077, a novel rhodacyanine dye in clinical trials, exhibits anticarcinoma activity in preclinical studies based on selective mitochondrial accumulation. 856 68

Investigation of the cytotoxic constituents of a two-sponge association (Poecillastra sp. and Jaspis sp.) led to the isolation of pectenotoxin II [1] and psammaplin A as the active compounds. In an in vitro cell culture assay, 1 displayed very potent cytotoxic activities against human lung (A-549), colon (HT-29), and breast (MCF-7) cancer cell lines. Pectenotoxin II also exhibited selective cytotoxicity against several cell lines representing ovarian, renal, lung, colon, CNS, melanoma, and breast cancer, with differences in LC50 values between sensitive and resistant cell lines of 100-fold or more.
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PMID:Cytotoxic compounds from a two-sponge association. 859 49

Numerous established human tumor lines co-express platelet-derived growth factor (PDGF) and cognate receptors, suggesting that an autocrine and/or paracrine growth mechanism may be a causal or contributing mechanism to their transformed phenotype. Indeed, it is known that a PDGF-autocrine system is functional in several established tumor lines, especially in human gliomas, and a model for a functional paracrine mechanism has been established in a human melanoma line. However, at least 168 human cell lines representing 26 different human tumor types have been reported to continuously express PDGF-A and/or -B chains, and 55 of these also express PDGF receptors. For the majority of these cases, the significance of co-expression and the relative roles of autocrine and paracrine mechanisms in transformation remains unclear. Here, we show that human glioblastoma T98G cells co-express PDGF-B/c-sis and moderate levels of the cognate beta-type PDGF receptor (PR-beta) but are not tumorigenic in athymic mice. In contrast, human breast carcinoma MCF-7 cells do not express PR-beta and are tumorigenic. Clonal lines of each cell type with greatly increased secretion of p16w(T98Gsis and MCF-7sis cells) were characterized. T98Gsis cells are 85% tumorigenic and occasionally develop pulmonary metastases, showing that endogenous PR-beta can mediate complete transformation upon sufficient stimulation. In contrast, MCF-7sis cells exhibit some growth slowing in vitro and an exactly proportional decrease in tumor growth rate. We conclude that a PDGF-autocrine, and not a paracrine, mechanism best accounts for the acquired tumorigenicity of T98Gsis cells, thereby emphasizing the potential significance of expression of even moderate levels of PR-beta by human tumor cells.
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PMID:Growth factor PDGF-B/v-sis confers a tumorigenic phenotype to human tumor cells bearing PDGF receptors but not to cells devoid of receptors: evidence for an autocrine, but not a paracrine, mechanism. 864 31

Human breast cancer is often characterized by a progression to an ER (estrogen receptor)-negative, estrogen-independent, antiestrogen-resistant, EGFR (epidermal growth factor receptor)-positive, and highly metastatic phenotype. The molecular and biochemical mechanisms behind this progression are not well defined. Most studies of breast cancer have focused on one or another aspect or this progression but have not found a common pathway. By constructing stable and complete human-human somatic cell fusions between a highly metastatic, undifferentiated, ER-negative line of melanoma lineage and the estrogen-dependent, ER-positive MCF-7 line, this study produced hybrids that were ER negative, highly expressive of EGFR, estrogen independent, estrogen unresponsive, fully tumorigenic, and highly metastatic. ER negativity was on the basis of complete suppression of ER transcription as evidenced by Northern blot analysis and nuclear run-on assay, not on the basis of gene rearrangement. EGFR positivity was not due to gene amplification or rearrangement but rather to increased EGFR transcription. Mechanisms, including ras activation, fibroblast growth factor 4 expression, and human DNA methyltransferase activation causing ER promoter methylation, which are respectively known to induce estrogen-independent growth, induce spontaneous metastasis, and decrease ER levels in breast carcinoma experimentally, were not mechanisms operating in the hybrids. This model demonstrates that many of the common denominators of human breast carcinoma progression can be regulated by dominant trans-acting factors.
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PMID:Human breast cancer progression can be regulated by dominant trans-acting factors in somatic cell hybridization studies. 875 27

Green tea is an aqueous infusion of dried unfermented leaves of Camellia sinensis (family Theaceae) from which numerous biological activities have been reported including antimutagenic, antibacterial, hypocholesterolemic, antioxidant, antitumor and cancer preventive activities. From the aqueous-alcoholic extract of green tea leaves, six compounds (+)-gallocatechin (GC), (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), (-)-epigallocatechin gallate (EGCG) and caffeine, were isolated and purified. Together with (+)-catechin, these compounds were tested against each of four human tumor cells lines (MCF-7 breast carcinoma, HT-29 colon carcinoma, A-427 lung carcinoma and UACC-375 melanoma). The three most potent green tea components against all four tumor cell lines were EGCG, GC and EGC. EGCG was the most potent of the seven green tea components against three out of the four cell lines (i.e. MCF-7 breast cancer, HT-29 colon cancer and UACC-375 melanoma). On the basis of these extensive in vitro studies, it would be of considerable interest to evaluate all three of these components in comparative preclinical in vivo animal tumor model systems before final decisions are made concerning which of these potential chemopreventive drugs should be taken into broad clinical trials.
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PMID:Inhibitory effect of six green tea catechins and caffeine on the growth of four selected human tumor cell lines. 882 14

A series of new 3'-(2-methyl-1-propenyl) and 3'-(2-methylpropyl) taxoids with modifications at C-10 was synthesized by means of the beta-lactam synthon method using 10-modified 7-(triethylsilyl)-10-deacetylbaccatin III derivatives. The new taxoids thus synthesized show excellent cytotoxicity against human ovarian (A121), non-small-cell lung (A549), colon (HT-29), and breast (MCF-7) cancer cell lines. All but one of these new taxoids possess better activity than paclitaxel and docetaxel in the same assay, i.e., the IC50 values of almost all the taxoids are in the subnanomolar level. It is found that a variety of modifications at C-10 is tolerated for the activity against normal cancer cell lines, but the activity against a drug-resistant human breast cancer cell line expressing MDR phenotype (MCF7-R) is highly dependent on the structure of the C-10 modifier. A number of the new taxoids exhibit remarkable activity (IC50 = 2.1-9.1 nM) against MCF7-R. Among these, three new taxoids, SB-T-1213 (4a), SB-T-1214 (4b), and SB-T-1102 (5a), are found to be exceptionally potent, possessing 2 orders of magnitude better activity than paclitaxel and docetaxel. The observed exceptional activity of these taxoids may well be ascribed to an effective inhibition of P-glycoprotein binding by the modified C-10 moieties. The new taxoid SB-T-1213 (4a) shows an excellent activity (T/C = 0% at 12.4 and 7.7 mg/kg/dose, log10 cell kill = 2.3 and 2.0, respectively) against B16 melanoma in B6D2F1 mice via intravenous administration.
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PMID:Syntheses and structure-activity relationships of the second-generation antitumor taxoids: exceptional activity against drug-resistant cancer cells. 883 55


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