Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The low-molecular-weight imidazoquinolinamine derivative, 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (imiquimod, previously described as R-837), induced alpha-interferon (IFN-alpha) in mice. IFN induction was identified at oral doses as low as 3 mg/kg. The 10% lethal dose for daily treatment with imiquimod was 200 mg/kg. Oral treatment with 30 mg/kg imiquimod once every three days significantly inhibited MC-26 colon carcinoma. Delay of treatment from day 1 to day 5, when tumors were easily palpable, did not reduce benefits. Ten daily treatments were slightly more effective than five. However, delivery of the same total dose of imiquimod either once every day for 20 days, once every 4 days, once every 7 days, or once every 10 days inhibited tumor growth to the same level. The antitumor effects of imiquimod were significantly abrogated by an antiserum to murine IFN-alpha, suggesting that the antitumor effect was to a substantial extent mediated by IFN induction. Imiquimod also significantly reduced the number of lung colonies in mice inoculated i.v. with MC-26 tumor cells. Combination of treatment with imiquimod and cyclophosphamide was significantly (P less than 0.01) better than treatment with either drug alone. Combination treatment with cyclophosphamide led to cures in some of the mice inoculated either s.c. or i.v. with MC-26 cells. Treatment with imiquimod also inhibited the growth of RIF-1 sarcoma and Lewis lung carcinoma but was ineffective for P388 leukemia. Imiquimod is an oral IFN-alpha inducer with antitumor effectiveness for transplantable murine tumors.
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PMID:Inhibition of murine tumor growth by an interferon-inducing imidazoquinolinamine. 137 95

The 1-O-octadecyl 2-O-methyl-sn-glycerophosphocholine (ET-18-O-CH3), when incubated for 24-48h with cells in culture, exerts a highly selective cytotonic activity against a variety of tumor cells that is not seen in normal ones. In this study, we present data which indicate that this exogenous molecule altered the endogenous synthesis of the neutral ether, ester-sn-glycerols, in 2 variant cell lines of a rat colon carcinoma. ET-18-O-CH3, at 20 microM in the medium and for an incubation of 48h, inhibited the growth rates of the PRO cells which have the ability to metastasize and of the REG cells (the regressive cell line), by, respectively, 54 and 67%, as measured after [3H] thymidine uptakes. The synthesis of the ether, ester-glycerolipids was followed after an incorporation of [3H] hexadecanol into the cell lipids. The radiospecific activity of the alcohol in the ether, ester-glycerolipids was higher for the PRO cells than for the REG cells. ET-18-O-CH3 activated the incorporation of [3H] hexadecanol in the neutral ether, ester-sn-glycerols: 1.55 fold in the PRO cells, but 2.15 fold in the REG cells. No change was observed in the alkyl (alkenyl) acyl-sn-glycerophospholipids. Most of the transformed cells have a low etherase activity and are known to accumulate the ether, ester-glycerolipids, (neutral and ionic structures).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine causes a differential incorporation of hexadecanol into neutral ether ester glycerolipids of 2 variant cell lines of rat colon carcinoma. 138 72

We have prepared a novel class of prodrugs by coupling 2'-deoxy-5-fluorouridine (5dFU) to oleic (18:1) and docosahexaenoic (22:6) acids, respectively. The cytotoxic activity of the drug and its conjugates (5dFU-18:1 and 5dFU-22:6) has been assayed in vitro upon HT-29, a colon carcinoma cell line of human origin. After short term (2-hr) treatments with the drugs, both fatty acid conjugates of 5dFU showed cytotoxic activity in a dose-dependent way, while 5dFU alone was devoid of toxic effects within the whole range of concentrations (10-200 microM) tested. Following long term (24- or 48-hr) incubations only a fraction of the HT-29 cell population was sensitive to 5dFU, the rest of the population being resistant even at the highest concentration tested (200 microM). In contrast, 5dFU-oleic acid and, particularly, 5dFU-docosahexaenoic acids appeared toxic for the whole population of HT-29 cells under the same experimental conditions. The considerable gain in cell toxicity and, to a lesser extent, in selectivity resulted from the conjugation since the toxic effect of the drug alone was not modified when equimolar mixtures of 5dFU and fatty acids were assayed. These results confirm a previous study on the cytotoxicity of fatty acid derivatives of chlorambucil toward malignant lymphoblastoid cells and reinforce the potential use of fatty acid conjugates as efficient anti-tumor prodrugs.
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PMID:Fatty acid conjugates of 2'-deoxy-5-fluorouridine as prodrugs for the selective delivery of 5-fluorouracil to tumor cells. 138 51

The possibility of using the porphyrin precursor 5-aminolevulinic acid to cause selective porphyrin accumulation in tumors was examined. Syngeneic colon carcinomas CC531 were implanted in the livers of Wag/Rij rats. Groups of three to six animals each were given 2 mg/mL of 5-aminolevulinic acid in drinking water from the 8th, 14th, or 17th day after tumor implantation. Two other groups received either 2.5 or 5 mg/kg of Photofrin II (Photomedica Inc., Raritan, NJ) intravenously on day 17. On day 19 the livers were removed and porphyrin concentrations were measured in normal livers and tumors by solvent extraction and high-performance liquid chromatography. Protoporphyrin accumulated progressively in tumors with increasing duration of 5-aminolevulinic acid administration (P = 0.0001), whereas no increase was found in normal livers. After 11 days of 5-aminolevulinic acid administration the porphyrin concentration ratio between tumors and livers was 4:1. In contrast, after Photofrin II administration the concentration was higher in normal livers than in tumors (1:3 ratio, tumor to liver). Enzyme measurements showed a threefold decrease in ferrochelatase activity in tumors compared with livers (P less than 0.001). In conclusion, oral administration of 5-aminolevulinic acid results in progressive accumulation of protoporphyrin in a transplantable colon carcinoma without accumulation in the surrounding liver tissue. This selective accumulation of porphyrins appears to be caused by a relative ferrochelatase deficiency in malignant tissue. 5-Aminolevulinic acid administration may be a suitable approach to photosensitizing liver tumors for photodynamic therapy or to early detection of tumors by fluorescence in ultraviolet light.
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PMID:Selective accumulation of endogenously produced porphyrins in a liver metastasis model in rats. 138 52

Using light and electron microscopy, we investigated the in vivo distribution of liposomes sterically stabilized by specific lipids which prolong their circulation in blood. Tissue distribution of sterically stabilized liposomes composed of distearoyl phosphatidylcholine:cholesterol:monosialoganglioside GM1 (10:5:1)-encapsulated 67Ga-Desferal indicates that more than 30% of liposomes still remain in the blood at 24 h after tail vein injection. Moreover, such liposomes accumulated in tumors (C-26 colon carcinoma cells implanted s.c.), reaching almost the same level of uptake as liver (approximately 20% injected dose/g tissue). The microscopic localization of liposomes labeled with encapsulated colloidal gold or rhodamine-labeled dextran coincided well with the tissue distribution. To evaluate circulation parameters, two sizes of gold-containing egg phosphatidylcholine:cholesterol:distearoyl phosphatidylethanolamine (derivatized at its amino position with a 1900 molecular weight segment of polyethylene glycol) (10:5:0.8) liposomes were injected. The plasma was examined by electron microscopy of negative-stained preparations at 0.5, 4, and 24 h after liposome injection. It was found that the ratio of small (less than 100 nm diameter) to large (greater than 100 nm) liposomes increased with time, indicating a much faster clearance of the larger liposomes. To detect the localization of liposomes in various tissues, appropriate samples were fixed 24 h after the injection of gold-containing liposomes (between 80 and 100 nm in diameter) composed of egg phosphatidylcholine:cholesterol:monosialoganglioside GM1 (10:5:1) or egg phosphatidylcholine:cholesterol:derivatized distearoyl phosphatidylethanolamine. The tissues examined for this study included normal liver, bone marrow, and implanted neoplasms. Silver-enhanced colloidal gold was found predominantly within Kupffer cells in the normal liver and within macrophages in the bone marrow. Rarely were any silver-enhanced gold particles detected in hepatocytes. In all preparations, electron microscopy revealed the presence of gold in endosomes and lysosomes of fixed sinusoidal lining macrophages in the liver and bone marrow. Peripheral to the implanted tumors, silver enhancement revealed gold in small blood vessels and focally beyond the vessel boundaries in extracellular spaces around tumor cells. Gold particles were not observed within the tumor cell cytoplasm. At the tumor border, nonenhanced gold was occasionally seen by electron microscopy in cells of the mononuclear phagocyte system. We obtained the same localization pattern as with silver enhancement by using an alternative aqueous content marker, rhodamine B isothiocyanate-dextran. We conclude that liposomes of specific composition, which have the ability to remain in circulation with a half-life of 12-24 h, are also able to transverse the endothelium of small blood vessels, including those in tumors, and extravasate into extracellular spaces.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Microscopic localization of sterically stabilized liposomes in colon carcinoma-bearing mice. 139 21

The distribution of O6-methylguanine-DNA methyltransferase (MGMT) activity in extracts of tumors from 74 patients was measured. The results demonstrated that there was considerable variation of MGMT activity in different human tumor tissues as well as in different individuals. The mean values (X +/- SD, pmol/mg of protein) in breast cancer, stomach cancer, small cell lung cancer, non-small cell lung cancer, renal cell carcinoma, esophageal carcinoma, brain tumors, colon carcinoma and malignant melanoma were 1.071 +/- 0.374 (9), 0.515 +/- 0.107 (5), 0.509 +/- 0.251 (5), 0.461 +/- 0.227 (24), 0.329 +/- 0.246 (5), 0.273 +/- 0.376 (5), 0.244 +/- 0.175 (14), 0.242 +/- 0.308 (5) and 0.201 +/- 0.161 (2) respectively. It was notable that six samples (1/24 non-small cell lung cancer, 3/5 esophageal carcinoma, 1/14 brain tumors and 1/5 colon carcinoma) did not have any detectable level of MGMT activity. Activity of glutamine pyruvic transaminase (GPT) was also measured in the same extracts used for the assay of MGMT activity. The activity of GPT in these samples with undetectable level of MGMT activity was similar to those with significant MGMT activity. These results further strengthen the assumption that a certain fraction of human tumors are Mer-.
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PMID:O6-methylguanine-DNA methyltransferase activity in human tumors. 139 31

Lymphokine activated killer (LAK) cells have been shown to exert a potent cytotoxic effect on many histologically different tumors and virally infected targets. Most normal cells but very few tumors have proven resistant to LAK lysis. The availability of two LAK resistant tumors, P815r, a murine mastocytoma, and SNUC-1, a human colon carcinoma, allowed us to study the phenomenon of LAK lysis. We examined the role of surface molecules on targets, which mediate binding to LAK cells, by cold target competition experiments and lectin dependent cellular cytotoxicity assays. The results showed that in the murine system, P815r cells do not compete for lysis of the LAK sensitive target B16 whereas other LAK sensitive murine targets compete. Alternatively, in the human system, SNUC-1 cells compete for lysis of the LAK sensitive target SNUC-4 as do other LAK sensitive human tumor cells. Furthermore, inducing binding of target and effector cells with lectin reverted the resistance of P815r but not SNUC-1 targets to lysis by LAK cells. These results imply that distinct stages of the lytic pathway might be involved in the resistance of different tumors to killing by LAK cells. The murine cell line is resistant to lysis because it cannot bind LAK cells. The human target, which does bind LAK, was insensitive to the effects of tumor necrosis factor alpha (TNF-alpha), a lymphokine released by LAK effectors and possibly involved in their lysis. Resistance to TNF-alpha was not mediated by the presence of endogenous short-lived proteins in the SNUC-1 targets. The elucidation of mechanisms of resistance may provide a tool to improve current protocols of adoptive immunotherapy as well as insights as to how tumor cells are or are not killed by LAK effectors.
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PMID:Resistance of different tumor cells to lysis by lymphokine activated killer cells can be mediated by distinct mechanisms. 139 42

The susceptibility to natural-killer-cell lysis and expression of histo-blood-group antigens of 2 clones from a rat colon adenocarcinoma, of variants derived from them and of 17 human colon carcinoma cell lines were assessed in an attempt to determine if the major glycosidic tissue antigens of epithelial cells could influence the NK susceptibility of tumor target cells of epithelial origin. The rat REGb clone, which is relatively NK-sensitive, expressed higher levels of precursor structures T and Tn and lower levels of H antigenic determinants than the PROb clone, which displays higher resistance to NK-cell lysis. Cell variants were obtained from these 2 clones; it appeared that whether the cell variants were selected on the basis of expression of a blood-group antigenic determinant or on the basis of altered susceptibility to NK-cell lysis, there was a link between increased resistance and higher expression of cell-surface A and H histo-blood-group antigens, or conversely, between increased sensitivity and higher expression of precursor structures. Similar conclusions were obtained upon study of the human cell lines, since a significant correlation was found between the level of expression of T or Tn antigens and sensitivity to NK-cell lysis. A significant relationship was found between the expression of Lewis antigens and increased resistance to NK-cell-mediated cytotoxicity.
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PMID:Involvement of histo-blood-group antigens in the susceptibility of colon carcinoma cells to natural killer-mediated cytotoxicity. 139 44

Expression of the cysteine proteinase cathepsin B and its physiological inhibitor cystatin C was analyzed in vitro in 1 human fibrosarcoma and 4 human colon carcinoma cell lines. Cystatin C antigen as well as cathepsin B activity were detected in the conditioned media of the 5 cell lines. The corresponding cell extracts expressed high levels of cathepsin B activity, whereas only trace amounts of cystatin C antigen could be found. Northern-blot analysis revealed the presence in the 5 cell lines of a 0.8-kb cystatin C mRNA transcript and 2 cathepsin B transcripts of 2.3 and 4.3 kb. Pepsin treatment of tumor-cell-released cathepsin B induced an average 7.3-fold increase in activity, indicating that the enzyme was mainly present as a latent form in conditioned medium. The pepsin-activated cathepsin B from one colon carcinoma cell line was further characterized using the cysteine proteinase inhibitors E-64, recombinant cystatin C, a cystatin-C-derived peptidyl inhibitor (Z-LVG-CHN2), and cathepsin-B-specific diazomethyl ketone inhibitors (Z-FT(OBzl)-CHN2, Z-FS(OBzl)-CHN2). This activity was totally neutralized by recombinant cystatin C, suggesting a potential for interaction between released extracellular cathepsin B and cystatin C. In vitro assays of degradation of extracellular matrix showed that cysteine proteinase inhibitors could decrease matrix degradation induced by pepsin-activated conditioned media. With colon cells, this inhibition was not observed, indicating a requirement for an extracellular activation of latent cathepsin B. Our data provide evidence that cystatin C and latent cathepsin B are both released extracellularly by colon carcinoma cells in vitro. They suggest that cystatin C and cathepsin B interactions may participate, in an as yet unelucidated way, in the modulation of the invasive phenotype of human colonic tumors.
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PMID:Cystatin C and cathepsin B in human colon carcinoma: expression by cell lines and matrix degradation. 139 47

Route of administration is an important determinant in tumor uptake of monoclonal antibody (mAb). We studied the extraction efficacy of intraportal injection (IP) on tumor uptake over time in hepatic metastases of human colon carcinoma (HT-29LMM) in nude mice. H-15, a murine IgG1 mAb reactive with HT-29LMM was labeled with I-125, and injected at dose of 0.1 microgram and 1.0 microgram intraportally (IP) or intravenously (IV). More than 3 animals per group were sacrificed immediately, 1 h, 24 h, 72 h, and 120 h following injection. Hepatic metastases, normal liver tissue, and blood were weighted and counted for radioactivity. Compared to IV, IP injection resulted in higher (P less than 0.01) percent injection dose per gram (%ID/g) in metastases at all time points for both doses. Metastases: blood and metastases: liver uptake ratios were higher (P less than 0.05) on day 3 and 5 for both IP doses compared to IV doses. Significant improvement in tumor uptake was seen following IP injection of specific mAb; this has important implications on the design of clinical trials using mAb.
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PMID:[Extraction efficacy on uptake of intraportally injected monoclonal antibody by human colorectal metastases in nude mice]. 140 78


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