Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007097 (carcinoma)
 152,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

N-methyl-dibenzo[c,g]carbazole (MeDBC) lacks the potent hepatocarcinogenic activity in mice characteristic for 7H-dibenzo[c,g]carbazole (DBC), while both compounds are local carcinogens, leading to papilloma and carcinoma formation in skin after topical application. Because DNA binding is considered an essential step in the initiation of chemical carcinogenesis, the DNA adduction by MeDBC was compared with that by DBC in mouse liver and skin via a 32P-postlabeling technique. Both compounds elicited chromatographically similar adducts in liver; however, the extent of total DNA binding of DBC was 343- and 265-fold greater than that of MeDBC 24 h after topical and i.p. administration, respectively, of a 37 mumol/kg dose. In skin, the adduct pattern elicited by either compound after topical application was different from that seen in liver, and three of four adducts derived from MeDBC were chromatographically distinct from those produced by DBC. Quantitative analysis revealed that total adduction in skin by DBC was 2.3-fold higher than by MeDBC. When the adduct levels were compared between liver and skin, topically applied MeDBC bound preferentially to skin versus liver DNA by a factor of 10, while the opposite was true for DBC. These data are in agreement with the carcinogenicity reported for DBC and MeDBC and support the hypothesis that the extent of covalent DNA modification by these compounds is associated with their biological activity. We conclude that an unsubstituted nitrogen is essential for the genotoxic activity of DBC in liver but not skin. The results also demonstrate the potential of the 32P-postlabeling assay in predicting the organotropism of closely related carcinogens.
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PMID:N-methylation reduces the DNA-binding activity of 7H-dibenzo[c,g]carbazole approximately 300-fold in mouse liver but only approximately 2-fold in skin: possible correlation with carcinogenic activity. 365 79

The hydroxyl-containing dithiocarbamates, sodium (di(hydroxyethl)-dithiocarbamate (NaY) and sodium N-methyl, N-dithiocarboxy-D-glucamine (NaG), appear to possess definite advantages over sodium diethyldithiocarbamate (DDTC) in reducing the cis-dichlorodiammineplatinum (Cis-Pt)-induced renal damage in rats given Cis-Pt as an IV bolus of 7.5 mg/kg 1 h before the IP administration of the dithiocarbamate. Renal damage, as estimated by blood urea nitrogen (BUN) values and serum creatinine levels, was less at all times up until sacrifice in animals given NaY or NaG than in those given DDTC. An even more effective method for suppression of Cis-Pt renal toxicity is to use a combination of procedures. The most efficacious combination involves a 24-h pretreatment with DDTC or NaG plus acetazolamide and normal saline hydration 30 min before administration of Cis-Pt, followed by post-treatment with NaG. With this combination therapy renal function can be almost completely spared. Although DDTC or NaG pretreatment is highly effective when used in conjunction with NaG post-treatment, DDTC or NaG pretreatment alone has no renal sparing effect on renal function or renal platinum accumulation. In experiments in which antidotes were given 1 h after Cis-Pt and the animals were followed up for 75 days, a chronic interstitial nephritis at 75 days, suggesting a persistent cell-mediated immune response to Cis-Pt-induced renal damage, may be the basis for chronically abnormal renal function resulting from Cis-Pt. Treatment with all three dithiocarbamates, NaY, NaG, and DDTC, reduced the intensity of this cellular reaction and also reduced platinum levels in the kidneys. Although NaY and NaG are effective heavy metal chelators and renal function is spared and kidney platinum levels are substantially reduced by the dithiocarbamates, no parallel loss of antineoplastic activity by Cis-Pt on the rat Walker carcinoma was observed. Since the dithiocarbamates have no known human toxicity that would disqualify their clinical use, phase 1 clinical trials are indicated.
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PMID:Inhibition of cis-diamminedichloroplatinum (II)--induced renal toxicity in the rat. 369 75

Cell killing, DNA-interstrand crosslinks, and DNA-protein crosslinks were assayed in nitrogen mustard-resistant Walker 256 carcinoma (WR) cells and the parent cell line (WS) after treatment with 5-[3-(2-chloroethyl)-1-triazenyl]imidazo-4-carboxamide (MCTIC). The WR cells, which also express collateral sensitivity to chloroethylnitrosoureas, were approximately twice as sensitive to the cytotoxic effects of MCTIC as were WS cells. Following treatment with 100 microM MCTIC, there was a rapid accumulation of both DNA-interstrand and DNA-protein crosslinks in the WR cell line, which reached a maximum at 6 and 12 hr, respectively. There was considerably less crosslinking in the WS cells and both cell lines were proficient in repairing most of the crosslinks by 24 hr. Measurement of guanine-O6-alkyl transferase activity showed the enzyme to be present in WS but not in WR cells. These data indicate that the collateral sensitivity of nitrogen mustard-resistant WR cells to chloroethylating drugs is in part due to the loss of guanine-O6-alkyl transferase activity which is present in the parent line.
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PMID:Selection of nitrogen mustard resistance in a rat tumor cell line results in loss of guanine-O6-alkyl transferase activity. 372 47

The safety and efficacy of pre-operative intravenous feeding using a peripheral venous infusion technique was evaluated in 15 black patients with oesophageal carcinoma. Energy requirements were based on individual energy expenditure at rest calculated from oxygen consumption and the respiratory quotient. Patients received 7 600 non-protein kJ and 9,4 g nitrogen daily for 14 days. Although no measurable improvements in nutritional status were noted after intravenous feeding, peripheral venous alimentation using the dual energy system proved an effective method of preventing progressive weight loss and depletion of the lean body cell mass. The infusion technique was safe and without serious metabolic or infectious complications. Total parenteral nutrition by peripheral venous infusion is a viable alternative to the central venous approach in patients with oesophageal carcinoma when their clinical and metabolic status demands early establishment of a positive nitrogen balance.
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PMID:Total parenteral nutrition by peripheral venous infusion in patients with oesophageal carcinoma. 392 Jul 62

In order to investigate the interactions of cytotoxic and other drugs, a cell culture assay was devised where changes in the ability of cytotoxic drugs to induce cytopathogenic effects can easily be visualized. A human mammary carcinoma cell line (BT 20) and a human hypernephroma cell line were used. Seventeen commonly used cytotoxic drugs were titrated in this assay. As an example of drug interactions the neutralization of nitrogen mustard, cis-dichlorodiammine-platinumII, and 4-hydroperoxycyclophosphamide by thiol-containing drugs shows that this assay is well suited to detect interactions of cytotoxic and other drugs.
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PMID:Interactions of cytotoxic and other drugs: rapid cell culture assay. 394 2

A Walker 256 rat carcinoma cell line (WR) with acquired resistance to nitrogen mustards has been found to lack cross-resistance to nitrosoureas. Although total cellular glutathione pools were similar in the parent (WS) and resistant cell lines (WS, 2.5 X 10(-6); WR, 2.0 X 10(-6) mol/mg protein), glutathione reductase activity was 3.98 in WR compared to 8.67 nmol reduced nicotinamide adenine dinucleotide phosphate oxidized per microgram protein per min in WS cells. Treatment of cells with a carbamoylating nitrosourea, N,N'-bis(trans-4-hydroxycyclohexyl)-N'-nitrosourea, produced a dose-dependent inhibition of glutathione reductase and depletion of thiols in both cell lines. The drug caused no direct DNA strand breakage, but a differential mitotic spindle-chromosome stain showed that spindle formation was inhibited in WR cells at N,N'-bis(trans-4-hydroxycyclohexyl)-N'-nitrosourea concentrations of greater than 50 microM. In WS cells, mitotic figures were still visible at 100 microM. Chromosomal damage was expressed in both cell lines at concentrations of 25 microM. The number and extent of these aberrations were greater in WR than WS. Observed karyotypic abnormalities included polyploidy, chromosome decondensation, and endoreduplication. In interphase cells, transmission electron microscopy showed that the most prevalent drug-induced lesions included (a) disappearance of plasma membrane filopodia, (b) appearance of membrane blebbing, and (c) development of irregular crescent-shaped nuclei. These morphological and cytogenetic changes correlate with cytotoxic responses of these cell lines to N,N'-bis(trans-4-hydroxycyclohexyl)-N'-nitrosourea and would be consistent with drug-induced inhibition of glutathione reductase.
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PMID:Carbamoylation of glutathione reductase and changes in cellular and chromosome morphology in a rat cell line resistant to nitrogen mustards but collaterally sensitive to nitrosoureas. 398 76

Estramustine [17 beta-estradiol 3 N bis(2-chloroethyl)carbamate; EM] is a stable conjugate of estradiol and nor-nitrogen mustard that is used for the treatment of human prostatic carcinoma. We have studied the cytotoxic effects of EM on the cytoskeletal organization of squirrelfish pigment cells (erythrophores) and human prostatic tumor cells (DU 145) in culture. Light and whole-mount electron microscopy studies reveal that, at microM levels (60 to 120 microM), EM has a dose-dependent disruptive effect on cell shape, cytoskeletal organization, and intracellular transport. Upon removal of the drug, the cytological effects of EM are rapidly reversible in fish cells but not DU 145s. Immunofluorescent studies reveal that EM produces microtubule disassembly in fish erythrophores and DU 145 cells. A concomitant disruption of actin-microfilament arrays also occurs in DU 145 cells. These morphological data suggest that EM, in contradistinction to its constituent estradiol: nitrogen mustard species, induces cytotoxicity as an antimicrotubule drug. The observed disruption of the microtubules and cytomatrix of interphase cells is not reversible in the prostatic carcinoma cells. The disruptive action of EM on the cytoskeleton could ultimately produce a cytotoxic antimitotic effect in dividing cells.
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PMID:Antimicrotubule effects of estramustine, an antiprostatic tumor drug. 401 56

A Walker 256 rat mammary carcinoma cell line (WR) resistant to bifunctional nitrogen mustards has been shown to have an approximate twofold increase in bulk glutathione-S-transferase activity compared to the parent cell line. Substrate specificity studies suggest that higher levels of Yb subunit contribute to the increased activity. By exposing WR cells to additional chlorambucil, either as a single concentration (50 micrograms/ml) or at 5 micrograms/ml for 10 days, transferase activity was further increased by up to three times the normal WR level. By using colony-forming assays, mitotic index depression, or trypan blue exclusion, the increased transferase activity could be correlated with an increase in resistance of these cells to either subsequent chlorambucil or a different bifunctional nitrogen mustard, phosphoramide mustard.
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PMID:Increased glutathione-S-transferase activity in a cell line with acquired resistance to nitrogen mustards. 401 71

Cyclophosphamide was introduced in 1958 in an effort to minimize the side effects of nitrogen mustard. Cyclophosphamide (Cytoxan, Endoxan) is not an alkylating agent which has been used for the treatment of a variety of non-malignant as well as malignant diseases. It has also recently been the focus of considerable interest as an immunosuppressive agent, perhaps the most potent immunosuppressive drug that has been synthesized. Reports of urologic complications from this drug are haemorrhagic cystitis, vesical fibrosis and urothelial carcinoma.
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PMID:Bladder carcinoma following cyclophosphamide therapy. A case report. 408 30

A scanning electron microscopic technique for the examination of bulk, fresh, hydrated human tissue is described. Samples of fresh tissue are frozen in liquid nitrogen against a mirror-finished copper block and planed in a cryoultramicrotome before transfer to a low temperature scanning electron microscope. After sublimation of water from the specimen surface, the tissue is examined in secondary electron and backscattered electron modes. Adjacent pieces of tissue, and those retrieved after backscattered electron observation, can be readily prepared for and examined by light and by conventional transmission electron microscopy. The method has been tested with multiple blocks taken from 6 cases of human breast carcinoma. In the backscattered electron mode, the infiltrating columns of neoplastic cells can be distinguished from mammary adipose and fibrous tissue. Within a carcinoma, the collagenous stroma, carcinoma cells, and perivascular and perineural infiltrates can be identified. These features have been contrasted with those obtained by light microscopy, by low temperature scanning, and by transmission electron microscopy. This use of backscattered electron imaging for the investigation of unfixed hydrated tissue offers the possibility that the technique could be of considerable value in the microscopy of very small samples in which, because of a need for subsequent biochemical, histochemical, and immunologic investigation, fixation and dehydration are to be avoided.
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PMID:Low temperature backscattered electron imaging in the study of human tissues. 608 28


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