Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001418 (adenocarcinoma)
 68,496 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The case of a 61-year-old male with repeated episodes of overt clinical lead poisoning and courses of chelation therapy during his 34 years of employment in a secondary lead smelter is presented. Renal function impairment with elevated serum creatinine and blood urea nitrogen and with markedly reduced glomerular filtration rate was detected several years before the discovery of a clear cell adenocarcinoma of the right kidney. After successful surgical removal of the tumor, the patient's renal function continued its previous trend of slow deterioration.
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PMID:Long-term occupational lead exposure, chronic nephropathy, and renal cancer: a case report. 734 29

Diastereomeric N,N'-dialkylbis(dichlorophenyl)ethylenediamines and the corresponding imidazolidines with chlorine in the 2,4, 2,6, 3,4, and 3,5 positions were synthesized. Only the stereoisomers of the 2,6-dichloro-substituted compounds exhibit for N-CH3 (2e, 3e), N-C2H5 (2f, 3f), and N-C3H7 (2g, 3g) an affinity to the estradiol receptor (Ka values ranging from 9.1 X 10(4) to 9.1 X 10(6)), because the nitrogen atoms are shielded by the ortho-located chlorine atoms; therefore, a binding interaction with hydrophobic receptor areas is possible. These substances show weak uterotrophic activity and no significant effect on the growth of the DMBA-induced hormone-dependent mammary adenocarcinoma of the rat.
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PMID:N,N'-Dialkylbis(dichlorophenyl)ethylenediamines and -imidazolidines: relationship between structure and estradiol receptor affinity. 745 88

Intraportal inoculation of CC531 adenocarcinoma cells into syngeneic rats causes an increase of liver macrophage cell number but not of major histocompatibility complex class II antigen expression. On day 1 after inoculation of 10(5) CC531 cells, a fixed number of isolated liver macrophages lysed significantly more target cells in vitro than did control cells. This effect was still present after 4 weeks. A 10-fold higher initial tumor dose significantly suppressed the macrophage response during the first 2 weeks. In contrast to tumoricidal activity induced by lipopolysaccharide in vitro, the tumoricidal response following in vivo challenge with tumor cells appeared not closely related to the production of reactive nitrogen intermediates, as in the latter case it was not abrogated in the presence of nitric oxide synthase inhibitor. Furthermore, the liver macrophage population appeared not fully activated after tumor inoculation as lipopolysaccharide further increased tumoricidal activity in vitro. The observed numerical and functional response of liver macrophages to intraportally inoculated tumor cells points at an important role of these cells in aspecific immune reactivity aimed at the reduction of local tumor growth. Results suggest that mechanistic differences exist between macrophage tumoricidal activity induced by tumor cells as compared with lipopolysaccharide.
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PMID:Tumoricidal response of liver macrophages isolated from rats bearing liver metastases of colon adenocarcinoma. 753 89

Recent evidence supports the critical and proximate role of IL-12 in regulating both T and NK cell function during inflammation. In these studies, we evaluated the in vivo antitumor activity of murine IL-12 in murine adenocarcinoma and sarcoma models using both systemic and peritumoral administration. Antitumor effects were consistently demonstrated both in models of microdisease, in which IL-12 treatment was initiated soon after tumor inoculation (1 to 5 days), and in animals bearing large established tumors (7 to 14 days). Treatment with IL-12 markedly prolonged survival and, in most cases, caused complete tumor regression. Significant reduction in pulmonary metastases after systemic treatment was observed when treatment was delayed for 10 days after tumor inoculation. Increases in serum IFN-gamma, TNF-alpha, and nitrogen oxides were demonstrated, exceeding those observed with IL-2 treatment. Systemic administration of anti-IFN-gamma Abs before IL-12 treatment nearly completely abrogated the antitumor effect in experiments using subcutaneous tumors or pulmonary metastases. Depletion of the individual T cell subsets CD4 and CD8 by systemic administration of mAbs diminished the effectiveness of IL-12 when administered in combination. An infiltrate composed primarily of CD8+ + cells was demonstrated by using immunohistochemical analysis of tumors after IL-12 treatment. Minimal apparent toxicity was demonstrated at effective doses (0.1 to 1.0 microgram/day) of IL-12. These results indicate that IL-12 is an effective and minimally toxic antitumor agent in murine tumor models and leads to an immune-mediated rejection involving, at least in part, IFN-gamma, CD4+, and CD8+ cells. Human clinical trials of IL-12 for the treatment of malignancy are supported by these studies.
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PMID:Recombinant IL-12 administration induces tumor regression in association with IFN-gamma production. 791 43

A series of analogues of the novel hypoxia-selective cytotoxin 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzamide (6) have been prepared and evaluated, in a search for compounds which retain high hypoxic selectivity but have increased potency and/or aqueous solubility. Several analogues with ionizable or dipolar carboxamide side chains showed improved solubility but generally had reduced cytotoxic potency and hypoxic selectivity. Modification of the mustard leaving groups or replacement of the carboxamide moiety provided some compounds with superior potency, but only the mixed chloro/mesylate mustard 20 provided a gain in potency relative to solubility while retaining the hypoxic selectivity of 6. These nitrogen mustards did not show the remarkable activity demonstrated by the related aziridine 7 [CB 1954, 5-(N-aziridinyl)- 2,4-dinitrobenzamide] in Walker 256 adenocarcinoma cells and are not efficient substrates for the DT-diaphorase which activates the latter compound by aerobic nitroreduction in Walker cells. Variations in hypoxic selectivity within the dinitrobenzamide mustards appear not to be due to differences in sensitivity to activation by this enzyme. Walker cells showed intermediate sensitivity to the mono(2-chloroethyl) analogue 26 but not to the related half-mustard 27, suggesting that the inhibition of DT-diaphorase activity is due to steric effects in the 5-position. The preferred compound overall with respect to solubility, potency, and in vitro hypoxic cell selectivity was the (dimethylamino)-ethyl derivative 11. DNA elution studies and comparison of the sensitivity of AA8 and UV4 cells to this compound indicated reductive activation to form a DNA cross-linking agent under hypoxia. Radiobiological studies indicated 11 to be equally active against both aerobic and hypoxic cells in KHT tumors. It is not clear whether this reflects efficient killing of aerobic cells as a result of diffusion of reduced metabolites from hypoxic regions or whether cytotoxicity in tumors is independent of hypoxia.
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PMID:Hypoxia-selective antitumor agents. 9. Structure-activity relationships for hypoxia-selective cytotoxicity among analogues of 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzamide. 803 24

AO-90, a methionine-free intravenous amino acid solution (7.43%) showed to potentiate the antitumor effect of 5-fluorouracil (5-FU) when concomitantly used as the nitrogen source in total parenteral nutrition (TPN) in Yoshida sarcoma (YS)-bearing rats. In the present experiment, this potentiation mechanism was studied by determining the serum methionine level and tumor methylenetetrahydrofolate (CH2FH4) content in YS-bearing Donryu rats given AO-90 (nitrogen 0.73g/kg on the 1st day and 1.46g/kg for the remaining 6 days) by TPN for 1 week. The rats were subcutaneously inoculated with 10(4) YS cells in the dorsum 3 days before the start of TPN. Inhibition of thymidylate synthase activity in tumor tissue after dosing of AO-90 (nitrogen 0.68g/kg on the 1st day and 1.36 g/kg for the remaining 6 days) by TPN along with daily intraperitoneal dosing of 5-FU (10 mg/kg) was also evaluated with the inoculation of 10(6) tumor cells. The results were compared with those in tumor-bearing rats given TPN with a commercially available amino acid solution containing methionine. On day 5 of TPN, the tumor-bearing rats given AO-90 showed a significantly lower serum methionine level than the control rats: 101 +/- 11 mumol/l versus 29 +/- 14 mumol/l (p < 0.01); and a higher CH2FH4 content in tumor: 7.0 +/- 2.8 pmol/g protein versus 23.7 +/- 16.6 pmol/g protein (p < 0.05). Thymidylate synthase inhibition was 81.2 +/- 5.1% in the AO-90 group and 30.9 +/- 26.3% in the control group (p < 0.01). The results of the present study suggest that AO-90 potentiate the antitumor effect of 5-FU by biochemical modulation. AO-90 concomitantly given with 5-FU for 7 days was effective not only in the allogeneic tumor model, but also in WKAH and SHR rats previously inoculated with 10(6) of syngeneic KDH-8 hepatoma cells and SST-2 adenocarcinoma cells, respectively. Weight of SST-2 adenocarcinoma in SHR rats after the TPN period was significantly smaller in the AO-90 group than in the control rats given methionine-containing TPN and 5-FU: 2.66 +/- 0.91 versus 5.12 +/- 2.11 (p < 0.05).
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PMID:[The mechanism of potentiation of the antitumor effect of 5-fluorouracil by methionine-free intravenous amino acid solution (AO-90) in rats]. 808 53

The present study establishes correlations of in vivo growth inhibition of a solid tumor, pancreatic ductal adenocarcinoma (Panc03), of mice with the steric and electrostatic fields and the hydrophobic parameter log P of a series (32) of 1-[[2-(dialkylamino)alkyl]amino]- 9H-thioxanthen-9-ones by the 3D-QSAR method comparative molecular field analysis (CoMFA). The template molecular model was hycanthone methanesulfonate (19), the structure of which had been established previously by X-ray crystallography. The hycanthone base is protonated at the terminal nitrogen N(2), and an intramolecular hydrogen bond is present between the proximal nitrogen N(1) and carbonyl oxygen O(1) atoms. Crystallographic data also indicate a planar arrangement of bonds around N(1). However, the molecular geometry of 19, optimized by semiempirical molecular orbital methods (PM3, MNDO, AM1), showed the expected trigonal-pyramidal configuration for N(1). A comparison of MO and ab initio methods applied to a model compound, 1-amino-9H-thioxanthen-9-one, led to the selection of PM3 as the method for full geometry optimization of first the cationic and then the neutral forms of 1-32, whereas AM1 provided atomic charges for these same structures save those incorporating a sulfonamide moiety (5, 7, 20, 25, 26, 29, 31, and 32). Acceptable values for the latter were obtained from ab initio calculations. Structures were aligned by minimizing root-mean-square (rms) differences in the fitting of structures to 19 using the FIT option of SYBYL. An alternative strategy of alignment, steric and electrostatic alignment (SEAL), was invoked to provide a comparison of statistical data generated with the rms alignment. The rms-fit alignment of structures produced slightly better cross-validated and conventional r2 values than those generated with the SEAL method. In addition, the rms-fit data indicate that a shift in the lattice of one-half of its spacing has a much smaller effect on the CoMFA data for a lattice of 1 A than one of 2 A. Inclusion of log P in a CoMFA of the neutral structures effected a small (ca. 8-10%) but significant improvement in cross-validated r2 values. The relative contributions of the hydrophobic effects and the steric and electrostatic fields to the conventional r2 values were 16%, 42%, and 42%, respectively. By contrast, incorporation of frontier molecular orbital (HOMO and LUMO) energies or their gaps in the PLS analyses failed to enhance correlation coefficients derived for either the charged or uncharged compounds.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Comparative molecular field analysis of the antitumor activity of 9H-thioxanthen-9-one derivatives against pancreatic ductal carcinoma 03. 814 27

The in vivo combination effect of navelbine (NVB, KW-2307) plus cisplatin was compared with that of vindesine (VDS) plus cisplatin in terms of antitumor activity and side effects. The antitumor activity of NVB or cisplatin against i.p. inoculated P388 leukemia was augmented by their combination on various schedules when the interval of administrations was within 24 h. Against i.v. inoculated P388 leukemia, the most significant combination effect was observed when cisplatin was administered 4 h after NVB injection (ILS(%) > 451) and three long-term survivors were observed. On this schedule, the combination of LD10 of each drug was achieved, indicating the lack of addition of toxicity. This was further proved by examination of body weight change, white blood cell count and platelet count. Interestingly, significant elevation of blood urea nitrogen concentration by cisplatin was prevented by the combination with NVB. The combination of maximum tolerated dose of NVB and cisplatin was also tolerable in nude mice, and their combination effect was observed against human lung large cell carcinoma Lu-65 and adenocarcinoma PC-12. The number of toxic death mice was more in VDS plus cisplatin-treated groups than in NVB plus cisplatin-treated groups, indicating that the combination chemotherapy of NVB plus cisplatin is a better regimen than that of VDS plus cisplatin in experimental tumor systems.
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PMID:Combination effect of navelbine (vinorelbine ditartrate) with cisplatin against murine P388 leukemia and human lung carcinoma xenografts in mice. 829 16

The effects of progressive cachexia on protein metabolism in skeletal muscle has been investigated in mice bearing the MAC16 adenocarcinoma which produces cachexia with tumour burdens of < 1% of the host weight. Weight loss was accompanied by loss of whole body nitrogen in proportion to the overall loss of body mass. Using L-[4-3H]phenylalanine to label proteins in gastrocnemius muscle, a significant depression (60%) in protein synthesis occurred in animals with a weight loss between 15 and 30% accompanied by an increase in protein degradation, which increased with increasing weight loss between 15 and 30%. Muscle degradation in vitro could be achieved by serum from cachectic animals, which appeared to contain a proteolysis-inducing factor. These results suggest that the increased degradation of skeletal muscle seen in this model of cachexia may be due to a circulating proteolysis-inducing factor.
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PMID:Increased protein degradation and decreased protein synthesis in skeletal muscle during cancer cachexia. 847 25

Metastatic prostate cancer which is refractory to hormone therapy remains an incurable disease for which there is no effective therapy. We have begun to investigate the nuclear matrix, the RNA-protein network of the nucleus that plays an important role in DNA replication and gene expression, as a target for cancer chemotherapy. It was postulated that estramustine phosphate (EMP), an estradiol-nitrogen mustard conjugate that binds to the nuclear matrix, might enhance the cytotoxicity of etoposide (VP-16), a topoisomerase II inhibitor that acts at the level of the nuclear matrix. In a nascent DNA synthesis assay, EMP and etoposide interact to selectively inhibit new DNA synthesis on the nuclear matrix. In vitro, EMP and etoposide appeared to act synergistically to inhibit the growth of the metastatic Dunning rat prostate adenocarcinoma cell line Mat-LyLu as well as the metastatic human prostate adenocarcinoma cell line PC-3. In vivo, EMP and etoposide inhibited prostate adenocarcinoma growth in the Dunning Copenhagen rat model. These data have formed the basis of a Phase I/II clinical trial to examine the effect of EMP and etoposide in patients with stage D hormone-refractory prostate cancer.
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PMID:Inhibition of prostate cancer growth by estramustine and etoposide: evidence for interaction at the nuclear matrix. 850 20


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