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)

Human melanoma cells, A375-C6, were "committed" to growth arrest within a few hours of exposure to interleukin-1 (IL-1). Co-treatment with actinomycin D rescued the cells from the "commitment," suggesting that "early" gene activation events may be crucial for growth arrest. To understand the mechanism of IL-1 action, we are studying early genes whose expression is induced by the cytokine. Five early genes associated with IL-1 action in the melanoma cells were isolated by differential screening of a cDNA library, which was enriched for sequences representing IL-1 responsive genes (IRGs). Nucleotide sequencing identified four of the genes as gro-alpha, gro-beta, c-jun and nur77/NGF1-B/NAK1, respectively, while the fifth was judged as novel by GenBank search and designated IRG-9. None of the early genes was uniquely associated with the antiproliferative action of IL-1: other growth-inhibitory as well as growth-stimulatory signals induced these genes in diverse cell types. However, analysis of the induction patterns of the IRGs and other well known early genes revealed that IL-1 action in the melanoma cells is characterized by activation of a unique primary gene expression program. This program was defined by the magnitude and temporal pattern of induction of the five IRGs, feeble induction of c-fos, and lack of induction of Egr-1 and c-myc. We present evidence that this program is growth arrest-specific in the melanoma cells and that distinct cell type-specific programs are associated with IL-1 growth-regulatory actions in other tumor cells. Based on these data, we propose that early genes may play multifunctional roles in tumor growth control, but specificity for the growth arrest action of IL-1 is determined by the composite early gene induction program.
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PMID:Interleukin-1-inducible tumor growth arrest is characterized by activation of cell type-specific "early" gene expression programs. 137 1

Synergy, when it can be convincingly established, is an effective strategy for the development of novel drug combinations. We have evaluated the interaction between 2'-deoxy-5-azacytidine (DAC) and 9-dimethylaminomethyl-10-hydroxycamptothecin (topotecan) based on our hypothesis that DAC, through DNA hypomethylation, might increase the transcription of topoisomerase I (topo I) leading to increased sensitivity to topotecan. Five human tumor cell lines, A375 melanoma, DX-3 melanoma, DMS4C non-small cell lung carcinoma, UP-1 unknown primary adenocarcinoma, SN12C renal carcinoma, and the murine CT-26 tumor cell line, were studied. Drug interactions were assessed using the multiple drug effect analysis of Chou and Talalay (Chors, T-C, and Talalay, P. Adv. Enzyme Regul., 22:27-54, 1984.). A synergistic interaction was documented in four human cell lines and the murine CT-26 line. An antagonistic interaction was observed with the SN12C cell line. The toxicology and efficacy of this combination were analyzed using CT-26 in BALB/c mice. Various treatment schedules were studied, including: single doses of each agent; single sequential combination treatments where DAC was administered followed by topotecan 24 h later; and multiple sequential treatments where DAC and topotecan were administered on days 1, 2, 8, and 9. Efficacy studies showed that the single sequential combination of DAC (50 mg/kg) and topotecan (10 mg/kg) resulted in tumor growth delay as compared to single doses of DAC (50 mg/kg) or topotecan (10 mg/kg). When the multiple sequential combination schedule was used, the antitumor effect was more pronounced. In that experiment 50% of the control animals had tumors of 20 mm by day 28. For animals receiving a single sequential treatment with DAC and topotecan, the median time until the mean tumor size reached 20 mm was 38 days, and for the group with multiple sequential combination treatments the time was 51 days. Studies of the mechanism of the interaction showed that the activity of topotecan versus each cell line correlated with the topo I activity in nuclear extracts However, there was no correlation between topo I levels and synergy and no reproducible increase in topo I activity following exposure to DAC. Thus, while the exact mechanism of the interaction remains unclear, DAC can be effectively combined with topotecan to enhance antitumor activity.
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PMID:Synergistic cytotoxicity with 2'-deoxy-5-azacytidine and topotecan in vitro and in vivo. 137 5

Histological data indicate the importance of tumor vascularization as a determinant of the biological behavior and the response to radiotherapy in choroidal melanoma. Duplex ultrasound and color Doppler imaging, the combination of B-mode ultrasound and pulse-waved Doppler analysis, were used to measure quantitatively neovascular blood flow in 31 patients with choroidal melanoma. Follow-up studies (20 patients) were performed to investigate the change of tumor blood flow in choroidal melanomas after radiotherapy. Blood flow was detected in 30 out of 31 melanomas (size 3.1-17.8 mm) within the tumor and at the tumor base with a mean peak systolic frequency of 1.0 kHz (range 0.3-2.7 kHz), a mean end diastolic frequency of 0.3 kHz (range 0.1-1.0 kHz), and a mean frequency of 0.7 kHz (range 0.2-1.3 kHz). Two and six months after 106Ru/106Rh beta-ray application, 19 patients showed a significant decrease in peak systolic frequency. This occurred with and in advance of the decrease in the tumor size. In one patient, a rising maximum systolic frequency after radiotherapy marked a recurrent tumor growth. Results indicate that the quantitative measurement of tumor blood flow by duplex ultrasound and color Doppler imaging may be a new diagnostic modality for monitoring the effectiveness of radiotherapy in choroidal melanoma.
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PMID:Quantitative color Doppler imaging in untreated and irradiated choroidal melanoma. 137 44

There is increasing evidence that cell-surface gangliosides play a role in tumor growth, progression and metastases. In order to determine the frequency of ganglioside GD3 in patients with metastatic malignant melanoma for further therapeutic trials, GD3 ganglioside expression was determined in 119 tissue samples. Of these melanomas, 93% (111/119) were R-24-positive, which indicates the value of this diagnostic marker for melanoma. To study the structural epitopes of gangliosides, 10 ganglioside antibodies with defined specificities and affinities were tested on over 100 fresh-frozen tissue specimens of human normal and melanoma tissues. All the antibodies tested recognize the ganglioside GD3, but vary in their cross-reactivity with other gangliosides. According to their epitope specificity, they can be divided into 5 groups. For example, the antibodies Z-21 and A-4 react like the previously established MAb R-24 with gangliosides GD3 and GQlb, and one MAb (Q-4) detects all gangliosides containing 2 connected sialic acids (GD3, GD2, GDlb, GTlb, GQlb). Specificity on TLC does not always correlate with specificity to melanoma tissues and vice-versa. For example, MAb A-4, which recognizes only GD3 and GQlb on TLC, shows no specific reactivity on tissues. Furthermore, antibodies with the same ganglioside specificity do not have the same staining pattern on human tissues. For example, MAb Z-21, which is directed against the same gangliosides as MAb R-24 on TLC, does not cross-react with as many neuroectodermal tissues as MAb R-24. Because of their distinct properties, some of these antibodies may be even more useful for immunodiagnosis and immunotherapy of malignant melanoma than MAb R-24.
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PMID:Immunorecognition of different ganglioside epitopes on human normal and melanoma tissues. 137 99

Interleukin 6 (IL-6) is a multifunctional cytokine important in the inflammatory response. Its potential role as an antitumor agent has been suggested by its demonstrated activity in a variety of tumor models. The mechanism of antitumor activity has been proposed to be its enhancement of cytotoxic T-cell function. In the current work we demonstrate clear antitumor activity for this cytokine in a nonimmunogenic tumor system. B16 melanoma cells transfected with the human IL-6 complementary DNA demonstrated slower tumor growth in vivo. Tumors that developed from these cells had a prominent stromal matrix, an easily recognized infiltration of inflammatory cells, fewer mitotic figures, and fewer blood vessels. These in vivo findings corresponded with a greater adhesion of the IL-6-transfected B16 cells to stromal matrix proteins (laminin, fibronectin, and vitronectin) and a less prominent vascular response in an intradermal angiogenesis assay. Therefore, we propose that with weakly antigenic tumors, such as B16 melanoma, IL-6 may mediate important antitumor responses by nonspecific proinflammatory mechanisms.
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PMID:In vivo and in vitro characteristics of interleukin 6-transfected B16 melanoma cells. 139 47

Tumors in general occur more frequently in older people, but many of the common tumors appear to be less malignant in older hosts. In this article mechanisms of tumor enhancement are reviewed, and those that are age-sensitive are emphasized. In this regard, our earlier experimental work suggested that age-associated immune change (immune senescence) is most important in explaining reduced tumor growth. We have found that unstimulated spleen cells in culture produce a tumor-enhancing factor (TEF) that enhances B16 murine melanoma cell proliferation. TEF, and others, such as lymphocyte-induced angiogenesis factor (LIA) and various other autocrine growth factors, may stimulate malignant cells in cancer-bearing hosts. An age-associated reduction in those factors could account for the observed reduced tumor growth and spread in hosts of advanced age.
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PMID:Explanations for reduced tumor proliferative capacity with age. 142 87

To evaluate new cytotoxic drugs for intrathecal treatment we developed an experimental model of leptomeningeal metastasis by intracisternal injection of 10(4) B16-F10 melanoma cells in nude rats. One hour in vitro incubation with 20 micrograms/ml ACNU (area under the drug concentration-time curve = 1200 microgramsxmin/ml) induced a 4-log kill of B16 melanoma cells. A single or repeated non-toxic dose of 1 mg/kg was injected into the cisterna magna of rats inoculated with tumor (area under the drug concentration-time curve assuming an even cerebrospinal fluid distribution greater than 7000 microgramsxmin/ml). Median survival free of symptoms was 16 days (range 14-27) for controls (n = 9) and 18 days (range 17-23) for rats treated with ACNU on day 4 (n = 9). Animals treated both on day 2 and 8 (n = 8) developed symptoms on day 21 (range 13-35). Neurological symptoms and neuropathological examination in animals with increased survival indicated local suppression of tumor growth in the cisterna magna but increased spinal seeding and mass growth. From these results and the available pharmacokinetic data on ACNU it is concluded that bolus injection of ACNU--although locally effective--is not a sufficient treatment of widespread leptomeningeal metastasis. An increased therapeutic efficacy might be achieved by ventriculolumbar perfusion.
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PMID:Intrathecal ACNU treatment of B16 melanoma leptomeningeal metastasis in a new athymic rat model. 143 39

The synergistic effect of local hyperthermia (LHT) with intratumor injection (i.t.) of cis-diamminedichloroplatinum (II) (DDP) was studied using a rodent model with implanted B16 melanoma tumors. The hindfoot of the C57BL/6 mouse bearing the tumor was placed in a water bath at 42.5 +/- 0.2 degrees C (intratumor temperature was at 42.3 +/- 0.1 degrees C) for 30 minutes just after local (i.t.) or systemic (intraperitoneal;i.p.) administration of DDP (1-3 mg/kg once in experiment I and 1-3 mg/kg three times in experiment II). The tumor growth ratio (TGR) at 7 days after treatment in the group given DDP 3 mg/kg (i.t.) with LHT was 1.1 in experiment I and 0.5 in experiment II, and there was a statistically significant difference in both experiments compared to findings in other groups (P < 0.01). The mean survival time was 42.1 days in experiment I and 50.2 days in experiment II, with a significant difference in the latter (P < 0.001). Thus regional injection chemotherapy given concomitantly with local hyperthermia promotes the anticancer effects and improves the prognosis without either severe renal injury or the promotion of hematogenic metastasis.
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PMID:Synergistic effects of intratumor administration of cis-diamminedichloroplatinum(II) combined with local hyperthermia in melanoma bearing mice. 143 45

Soluble forms of receptors for the Fc portion of IgG (sFc gamma R) were detected in biological fluids from mice and humans. In mouse bearing tumors, circulating amounts of sFc gamma R increased concurrently with tumor growth. Tumors secreting IgG2a, IgG2b or IgG3 led to a 5- to 10-fold increase in serum sFc gamma R levels whereas tumors secreting IgG1, IgGA or other types of tumors (non Ig B cell tumors, T cell lymphoma and a melanoma) increased 2- to 3-fold the levels of circulating sFc gamma R. In the human, sFc gamma R were also detected in whole unstimulated saliva. Levels of sFc gamma RII and of sFc gamma RIII were variable and did not seem to depend on the dental status of the individuals. Finally, a murine recombinant sFc gamma R (rsFc gamma R) composed of the two extracellular domains of Fc gamma RII was produced by culture of transfected L cells in bioreactors. The purified rsFc gamma R was found to inhibit antibody production in vitro in anti-SRBC responses and by cultures of small B cells stimulated by anti-IgM antibodies in the presence of IL-4 and IL-5. Moreover, the i.p. injection of this material into adult mice immunized with SRBC led to a decrease of IgG antibody production by splenocytes, as measured by a hemolytic plaque assay, and in serum, as measured by antigen-specific ELISA.
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PMID:Soluble Fc gamma R (sFc gamma R): detection in biological fluids and production of a murine recombinant sFc gamma R biologically active in vitro and in vivo. 145 2

Eye tumors of the retinal pigment epithelium (RPE) have been thought generally to be benign, whereas choroidal ones are malignant. To test this assumption in mice, the W/Wv (Kit) mutant genotype was introduced into melanoma-prone transgenic mice whose recombinant simian virus 40 transforming sequences are specifically expressed in pigment cells. W/Wv causes programmed death of neural crest-derived pigment cells, including choroidal ones, but leaves intact the brain-derived pigment cells, such as those in the RPE. Dysplastic cells arose in the RPE, contiguous with frank melanotic neoplasms. Invasion of the optic nerve, and tumor growth outside the orbit, attested to the malignancy of these RPE-derived melanomas. The widespread melanosis previously seen in mice with this transgene was absent when W/Wv was added, thus validating its chief origin from neural crest cells.
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PMID:Malignancy of eye melanomas originating in the retinal pigment epithelium of transgenic mice after genetic ablation of choroidal melanocytes. 145 29


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