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)

Bryostatin 1, a macrocyclic lactone, has undergone phase I trials as an anticancer agent. Because of the lipid solubility of this compound it must be delivered either in ethanol or in a PET formulation. During the trial, these vehicles caused a large number of treatment-related side effects. We have synthesized the triethanolamine salt of 26-succinylbryostatin 1 and find that this compound is approx. 100-fold more water soluble than bryostatin 1. Because of the potential for clinical use, we have evaluated the biologic activity of this compound. We find that in a concentration-dependent manner 26-succinylbryostatin 1 is capable of activating protein kinase C (PKC) in vitro and displacing [3H]PDBu from PKC. However, at all concentrations tested the activity was less than the parent compound bryostatin 1. Addition of bryostatin 1 but not 26-succinylbryostatin 1 to U937 leukemic cells in culture stimulated a drop in cytosolic PKC, secondary to translocation of PKC to the membrane. Although 26-succinylbryostatin 1 did not stimulate a drop in the cytosolic levels of PKC, addition to U937 cells activated transcription from an AP-1 enhancer construct and c-Jun protein phosphorylation in a similar fashion to bryostatin 1 and differentiation of U937 cells. Unlike bryostatin 1, 26-succinylbryostatin 1 was unable to cause aggregation of human platelets. Although injection of bryostatin-1 into mice carrying B16 melanoma inhibits tumor growth, there was no significant inhibition of melanoma growth when identical doses of 26-succinylbryostatin 1 were injected. Therefore, 26-succinylbryostatin 1 shares some but not all of the pharmacologic properities of bryostatin 1. This compound can activate protein phosphorylation without lowering cytosolic levels of PKC.
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PMID:Biological activity of 26-succinylbryostatin 1. 870 88

A cohort of 30,940 male and 11,529 female seafarers registered in the files of Seafarers' Pension Fund in Finland was followed up through the Finnish Cancer Registry for cancer in 1967-92. Among male seafarers, there were 1,199 cases of cancer, which corresponds to the average cancer incidence in Finnish men. There was a statistically significant excess of non-melanoma skin cancer (standardized incidence ratio [SIR] = 1.8, 95 percent confidence interval [CI] = 1.2-2.5) and mesothelioma (SIR = 2.9, CI = 1.2-5.6) in the follow-up category of 20 or more years since the first employment. Alcohol-related cancers were increased among seafarers (SIR for cancer of the mouth and pharynx = 1.5; esophagus = 1.4; and liver = 1.5; combined CI = 1.1-1.9). Deck crews had a significantly high risk of cancer of the pancreas (SIR = 2.0) and also prostate after 10 years since first employment (SIR = 1.6). Occupational asbestos exposure among seafarers is likely strong enough to cause excess cases of mesothelioma but not of lung cancer. Occupational exposures also may be associated with increased risk of cancers of the kidney, pancreas, prostate and old-age brain cancer in some of the main occupational categories. Cumulative ultraviolet radiation likely doubles the risk of non-melanoma skin cancer among older men and repeated sunburns that of skin melanoma in ages below 30 (SIR among deck and engine crew = 4.6, CI = 3.1-6.5). Female ship personnel had a significantly elevated total cancer risk (observed number of cases = 732) which increased over follow-up time (SIR in the category > or = 20 years since the first employment was 1.3, CI = 1.1-1.5). This excess was attributable primarily to lung cancer (SIR = 2.6, CI = 2.0-3.3). Also cancers of the cervix uteri, vulva, and vagina showed significant excess after 10 to 20 years since first employment aboard.
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PMID:Cancer incidence among Finnish seafarers, 1967-92. 874 Jul 36

Targeted drug delivery systems combining thermosensitive liposome-entrapped anticancer drugs and hyperthermia have been tried for targeting drugs to tumors. These heat-sensitive liposomes are prepared from synthetic lipids. Herein we report the use of thermosensitive liposomes composed of natural lipids, viz., egg phosphatidyl choline, cholesterol, and ethanol, having phase transition temperature of 42.7 degrees C for targeted drug delivery. The antitumor effect of melphalan encapsulated in thermosensitive small unilamellar liposomes administered in combination with hyperthermia was studied in C57B1/6 mice bearing B16F10 melanoma. The in vivo efficacy of liposome-encapsulated melphalan in combination with hyperthermia as measured by reduction in tumor volume and increased survival time was greater than that of an equivalent concentration of free melphalan with or without heating. These results suggest that the combination of drug-loaded natural lipid-derived thermosensitive liposomes with local hyperthermia at the tumor site could be useful in enhancing drug delivery to tumors and improving its therapeutic efficacy in treatment of solid tumors.
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PMID:Hyperthermia-mediated targeted delivery of thermosensitive liposome-encapsulated melphalan in murine tumors. 874 2

The experimental metastatic potential (lung-colonizing ability) of B16BL6 melanoma cells was examined in C57BL/6 mice after exposure to ethanol in vitro and in vivo. In vitro, tumor cells were cultured with ethanol (0.3% v/v), or medium alone, for three passages at 5-day intervals. In vivo, B16BL6 melanoma was exposed to ethanol by administering ethanol (10% or 20% w/v) to mice following subcutaneous inoculation of tumor cells into the dorsal hip. All tumor cells were subsequently inoculated intravenously into the lateral tail vein of water-drinking mice to assess changes in metastatic phenotype. Tumor cells cocultured in vivo with ethanol produced significantly higher numbers of superficial lung colonies, compared with tumor cells cultured in control medium. Experimental metastasis of tumor cells obtained from 20% w/v ethanol-consuming mice was also significantly increased, compared with cells obtained from water-drinking mice. Metastasis of B16BL6 melanoma cells previously obtained from mice consuming 10% w/v ethanol did not differ from controls. In other experiments, water-drinking and ethanol-consuming (2.5%, 10%, and 20% w/v) mice were inoculated subcutaneously into the dorsal hip with B16BL6 melanoma cells, and monitored for tumor growth rate and survival time. In these experiments, survival times were significantly shorter in mice consuming 20% ethanol, compared with all other groups. Subcutaneous tumor growth rate was unaffected by ethanol consumption. Lung metastasis resulting from subcutaneous tumor implantation of B16BL6 melanoma was respectively inhibited, or absent, in 10% and 20% ethanol-consuming groups. Thus, tumor growth rate and incidence of lung metastases were not apparent determinants of decreased survival in 20% ethanol-consuming mice. The results of this study indicate that the experimental metastatic potential of B16BL6 melanoma is increased during exposure to ethanol; however, metastasis from subcutaneous tumor-bearing mice is suppressed. This latter finding is consistent with previous results in which spontaneous metastasis was also suppressed after inoculation of the tumor into the pinna of the ear. Although ethanol increases the ability of B16BL6 melanoma to colonize the lung after intravenous inoculation, this effect is abated in the presence of host factors in ethanol-consuming mice.
Alcohol Clin Exp Res 1996 Jun
PMID:Ethanol modulates metastatic potential of B16BL6 melanoma and host responses. 880 Mar 77

Earlier evidence suggests that transforming growth factor beta (TGF beta) plays a significant role in tumor progression and metastasis. The most likely mechanism of the action of TGF beta is induction of immunosuppression in the host, allowing for unchecked tumor growth and metastasis. We attempted to test that hypothesis and to compare antitumor effects of anti-TGF beta antibody alone and in combination with interleukin-2 (IL-2). Six- to 8-week-old female C57B1-6 mice were induced with murine B16 melanoma by tail vein injection. Therapy was started 48 h after tumor injections. Monoclonal anti-TGF beta antibody (2G7) was administered intraperitoneally (i.p.) at 500 micrograms every other day, and IL-2 at 10,000 U i.p. twice daily, for 21 days. A threefold decrease in the number of lesions in the anti-TGF beta/IL-2 treatment group compared with the control group was observed, a highly significant statistical difference (p = 0.002). No statistically significant differences were seen between the control group and other studied groups (IL-2 alone, anti-TGF beta alone). Analysis of TGF beta levels in plasma by the TGF beta-1 Quantikine assay indicated normal levels in the control and IL-2 groups, and significantly diminished levels in the two groups that received TGF beta antibody. However, acid-ethanol extraction of plasma (to reverse antibody binding before assay) showed normal plasma TGF beta levels in all groups, suggesting that the antibody may alter the availability of TGF beta in vivo. Microscopic analysis of metastases revealed a decrease in the average size of lesions in the groups treated with IL-2. Thus, combination therapy using anti-TGF beta antibody and IL-2 may be a novel, less toxic approach to tumor immunotherapy.
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PMID:Modulation of B16 melanoma growth and metastasis by anti-transforming growth factor beta antibody and interleukin-2. 881 91

Recent epidemiologic data confirm the results of earlier studies in supporting that alcoholic beverage consumption is a cause of cancer of the mouth, pharynx, larynx, esophagus, and liver. The effect of a specified level of alcohol intake on absolute risk of cancers of the head, neck, and esophagus depends on the presence of other risk factors, especially smoking. Whether alcoholic beverage consumption is a cause of cancer of the breast or large bowel is unclear. Alcohol intake appears not to increase risk of cancer of the lung, bladder, prostate, stomach, ovary, endometrium, or of melanoma. Indirect epidemiologic evidence suggests that alcohol may be a weak causal factor for pancreatic cancer. Although heavy alcohol consumption increases risk of cancer of the head, neck, esophagus, and liver, whether moderate alcohol consumption increases risk at these sites is unclear.
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PMID:Epidemiologic data on alcoholic beverage consumption and risk of cancer. 881 61

Percutaneous injection of absolute ethanol was found to cause rapid destruction of murine and human melanoma nodules. It took only 24-48 hr after the ethanol injection to form ulcers or scars on the lesions. Massive necrosis of murine and human melanoma nests and interstitials and infiltration of mononuclear cells into the demaged tissue were observed histopathologically after ethanol injection. The melanomas recurred approximately 1 week after the destruction of the melanoma nodules by ethanol. Biological response modifiers such as levamisole or interleukin (IL)-2 were effective in preventing the recurrence of murine melanoma after ethanol injection. IL-2 injection caused massive infiltration of NK cells, T cells, and macrophages into the damaged melanoma tissue. The therapeutic modality of a combination of ethanol and IL-2 injections could definitely be useful for the local treatment of human metastatic melanoma, but other modalities such as local hyperthermia or radiation should be considered in combination to attain a permanent cure.
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PMID:Rapid destruction of murine and human melanomas by local injection of absolute ethanol: augmentation of the anti-proliferative effects with a combination of biological response modifiers. 893 25

Taxol is a novel antitumor alkaloid that has shown clinical activity against several tumors. However, due to its low aqueous solubility, Cremophor EL (polyoxyethylated castor oil) and ethanol are used as excipients in the pharmaceutical drug formulations. These agents are implicated in hypersensitivity reactions. Hence the goal of this work was to design a novel Taxol formulation using polymeric nanoparticles to eliminate the Cremophor EL vehicle for drug delivery. Polyvinylpyrrolidone nanoparticles containing Taxol were prepared by a reverse microemulsion method. The size of the nanoparticles as determined by quasielastic light scattering was found to be between 50 and 60 nm. The antitumor effect of Taxol encapsulated nanoparticles was evaluated in B16F10 murine melanoma transplanted in C57B1/6 mice. The in vivo efficacy of Taxol-containing nanoparticles as measured by reduction in tumor volume and increased survival time was significantly greater than that of an equivalent concentration of free Taxol. These results suggest that encapsulation of Taxol in polymeric nanoparticles could be useful in improving its therapeutic efficacy in treatment of solid tumors.
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PMID:Novel Taxol formulation: polyvinylpyrrolidone nanoparticle-encapsulated Taxol for drug delivery in cancer therapy. 893 91

Iron (Fe) chelators of the pyridoxal isonicotinoyl hydrazone (PIH) class may be useful agents to treat Fe overload disease and also cancer. These ligands possess high activity at mobilizing 59Fe from neoplastic cells, and the present study has been designed to examine whether their marked activity may be related to an energy-dependent transport process across the cell membrane. Initial experiments examined the release of 59Fe from SK-N-MC neuroblastoma (NB) cells prelabelled for 3 h at 37 degrees C with 59Fe-transferrin (1.25 microM) and then reincubated in the presence and absence of the chelators for 3 h at 4 degrees C or 37 degrees C. Prelabelled cells released 4-5% of total cellular 59Fe when reincubated in minimum essential medium at 4 degrees C or 37 degrees C. When the chelators desferrioxamine (DFO; 0.1 mM) or PIH (0.1 mM) were reincubated with labelled cells at 4 degrees C, they mobilized only 4-5% of cellular 59Fe, whereas as 37 degrees C, these ligands mobilized 21% and 48% of cell 59Fe, respectively. The lipophilic PIH analogue, 311 (2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone; 0.1 mM), which exhibits high anti-proliferative activity, released 10% and 53% of cellular 59Fe when reincubated with prelabelled cells at 4 degrees C and 37 degrees C, respectively. Almost identical results were obtained using the SK-Mel-28 melanoma cell line. These data suggest that perhaps temperature-dependent mechanisms are essential for 59Fe mobilization from these cells. Interestingly, the metabolic inhibitors, 2,4-dinitrophenol, oligomycin, rotenone, and sodium azide, markedly decreased 59Fe mobilization mediated by PIH, but had either no effect or much less effect on 59Fe release by 311. Considering that an ATP-dependent process was involved in 59Fe release by PIH, further studies examined 4 widely used inhibitors of the multi-drug efflux pump P-glycoprotein (P-gp). All of these inhibitors, namely, verapamil (Ver), cyclosporin A (CsA), reserpine (Res) and quinine (Qui), decreased 59Fe mobilization by PIH but had little or no effect on 59Fe release mediated by analogue 311. Further, both CsA and Ver increased the proportion of ethanol-soluble 59Fe within cells in the presence of PIH, suggesting inhibited transport of the 59Fe complex from the cell. However, when PIH-mediated 59Fe release was compared between a well characterized Chinese hamster ovary cell line (CHRB30) expressing high levels of P-gp and the relevant control cell line (AuxB1), no appreciable difference in the kinetics of 59Fe release were found. In contrast, it was intriguing that the CHRB30 cells released more 59Fe into control medium (i.e., without PIH) than the AuxB1 control line (16.7% compared to 5.9%, respectively). In summary, the results suggest that a temperature- and energy-dependent process was involved in the efflux of the PIH-59Fe complex from the cells. In contrast, 59Fe release mediated by 311 was temperature-dependent but not energy-dependent, and could occur by simple diffusion or passive transport. Further studies investigating the membrane transport of Fe chelators may be useful in designing regimes that potentiate their anti-neoplastic effects.
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PMID:Mobilization of iron from neoplastic cells by some iron chelators is an energy-dependent process. 918 79

Malignant melanoma are chemoresistent tumors with poor prognosis. The aim of this study was to determine whether multimodality therapy of murine melanoma involving a combination of radiation with thermosensitive-liposome-encapsulated melphalan and local hyperthermia would result in enhancement of therapeutic efficacy for a more effective management of melanoma. Melphalan was entrapped in thermosensitive liposomes prepared from natural lipids: egg phosphatidyl choline, cholesterol and ethanol to show phase transition at 42 +/- 0.5 degrees C and used in combination with localized heating of B16F10 murine melanoma transplanted into the legs of C57B1/6 mice for selective drug targeting at the tumors and/or radiation for treatment of melanoma. Murine melanoma transplanted into C57B1/6 mice were subjected to bimodality treatments involving a combination of radiation, hyperthermia or melphalan. Partial tumor regression was observed in mice receiving a combination of hyperthermia and radiation (median tumor volume 427.3 mm3) or a combination of free melphalan and radiation (512.1 mm3) as compared to untreated controls (630.9 mm3). Each group consisted of 18 animals, and the results are expressed as median tumor volume +/- SD. Animals receiving multimodality therapy comprising irradiation followed by injection of thermosensitive liposomal melphalan and hyperthermic treatment of the tumor-bearing leg at 42 +/- 0.5 degrees C for 1 h showed marked tumor regression in comparison with untreated controls or animals treated with a combination of radiation and hyperthermia or radiation and free-drug melphalan. Animals receiving thermoradiochemotherapy also showed prolonged survival; 70% of animals survived for more than 3 months. The study shows greater tumor cell killing, tumor growth delay and prolonged survival produced by a combination of radiation, thermosensitive-liposome-entrapped melphalan and hyperthermia compared with animals receiving single-modality or bimodality treatments. It is concluded that this multimodality approach will be potentially useful for more effective management of melanoma.
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PMID:Hyperthermia potentiates antitumor effect of thermosensitive-liposome-encapsulated melphalan and radiation in murine melanoma. 921 10


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