Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0006142 (breast cancer)
160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neovascularization and hemorrhage are common features of malignant tumors. We wondered whether hemoglobin derived from extravasated RBC deposits heme-derived iron into the tumor, which could modulate the sensitivity of cancer cells to oxidant-mediated injury. A brief exposure (1 h) of 51Cr-radiolabeled breast cancer cells (BT-20) but not colon cancer cells (Caco-2) to hemin (10 microM) or FeSO4 (10 microM) significantly enhances cytotoxicity mediated by 0.5 mM hydrogen peroxide (H2O2). Associated with Caco-2 resistance, these cells were found to be enriched in the endogenous iron chelator, ferritin. If cellular ferritin is even further increased through 1 h incubation (24 h prior to H2O2 exposure) of both cell types with hemin, FeSO4, or exogenous spleen apoferritin itself (24 h), marked resistance to H2O2-mediated cytotoxicity is manifest. Under several conditions, the sensitivity of tumor cells to oxidant-mediated lysis is inversely proportional to their ferritin content. Pretreatment of BT-20 and Caco-2 cells with hemin or FeSO4 rapidly increases H-ferritin mRNA but only slightly increases L-ferritin mRNA; nevertheless, large increases in overall ferritin content of iron-exposed cells result. Data analogous to those with H2O2-mediated cytotoxicity were obtained in studies of bleomycin-engendered DNA strand breakage and cell damage, i.e., brief treatment of BT-20 cells with both hemin or FeSO4 significantly increases their sensitivity to bleomycin (100 micrograms/ml), whereas treatment followed by 24 h incubation with media alone significantly protects against bleomycin toxicity. We speculate that acute exposure of tumors to iron (e.g., derived from heme-proteins in hemorrhagic cancerous lesions) may increase sensitivity of some cancer cells, particularly those relatively low in endogenous ferritin, to oxidant-mediated lysis. In contrast, repeated, more chronic, exposure effector cells or chemotherapeutic agents, an effect derived from their increased synthesis and accumulation of the intracellular iron scavenger, ferritin.
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PMID:Tumor cell heme uptake induces ferritin synthesis resulting in altered oxidant sensitivity: possible role in chemotherapy efficacy. 822 66

Transferrin receptors on proliferating and malignant cells are well documented. Iron is an essential micronutrient for cell growth that plays an important role in energy metabolism and DNA synthesis. Malignant cells requiring more iron modulate a transferrin receptor. Iron-bound transferrin interacts with this receptor, facilitating the transport of iron across the cell membrane. Transferrin is a glycoprotein and is the chief iron transport protein in mammalian blood. The more aggressive the tumor, the higher the transferrin receptor levels and the greater the proliferative index. We have found by cytochemical and ultrastructural studies that ferritin, an iron storage protein, is increased in breast cancer tissue. Anaplastic tumors have higher tissue ferritin levels. Tissue ferritin concentration may be an indirect method of measuring transferrin receptors and thus might be an index of proliferation and a prognostic indicator. Transferrin may be used as a carrier to target toxic therapy selectively to tumor tissue. A platinum transferrin complex (MPTC-63) has been developed and shown to be cytostatic in tissue culture, animal, and human studies. It also sensitizes tissue to agents that produce free radicals, such as adriamycin, and thus is synergistic with other drugs and radiation. Other transferrin complexes and conjugates of gallium, indium, and daunorubicin have also shown growth inhibition in tissue culture and animals. Human studies are in progress. By studying iron metabolism in breast cancer, we may be able to selectively inhibit tumor growth without toxic effects, and with other tumor biologic data be better able to select the stage I patient for adjuvant therapy.
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PMID:Breast carcinoma and the role of iron metabolism. A cytochemical, tissue culture, and ultrastructural study. 827 55

Suprathreshold taste perception and nutrient intake were assessed for two groups of women aged 44 to 56 years: 24 mastectomized breast cancer outpatients and 24 matched controls. Salty and sweet taste intensity and pleasantness were evaluated in aqueous solutions and simple foods by unstructured line scaling. Dietary intakes were assessed by combined dietary recall (1 day) and food record (3 days). Suprathreshold taste intensity and pleasantness data did not differ between the breast cancer and control groups. Breast cancer subjects consumed less energy and were at greater overall nutritional risk than the controls. Compared with control subjects, breast cancer subjects were at greater risk of calcium and iron deficiency. Regression analysis was used to investigate relationships between diet and taste for a breast cancer subgroup (n = 7) with unusually low energy intake (< or = 1,300 kcal/day) and a high overall nutritional risk (25.6%). For the subgroup, significant relationships between taste and diet were found, although taste data did not differ from that of the controls. Percent risks of nutrient deficiency for vitamin B-12, thiamin, folacin, iron, and riboflavin were important predictors of taste-intensity slopes for the cancer subgroup. Findings suggest that for some of the breast cancer subjects, diet may be associated with unsatisfactory nutritional status and may be affected by suprathreshold taste perception.
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PMID:Taste perception and breast cancer: evidence of a role for diet. 831 63

We have investigated the nature of lipid peroxidation occurring in association with cancer-killing produced by gamma-linolenic acid (GLA) and iron (Fe) in cultured human breast cancer cells (ZR-75-1: ZR). UV-spectrophotometry, high performance liquid chromatography (HPLC) and gas chromatography (GC) or gas chromatography-mass spectrometry (GC-MS) have been used to analyze lipid peroxides and their derivatives. Formation of conjugated dienes (CD), the conversion of triphenylphosphine (TPP) to its oxide (TPPO), and the simultaneous production of hydroxy polyunsaturated fatty acids (PUFA-OHs) from these corresponding PUFAs hydroperoxides (PUFA-OOHs) were analyzed in the total lipid extract of ZR cells and of normal human skin fibroblasts (CCD-41Sk:Sk). Fe enhanced the formation of both the CD and TPPO and increased the percentage of dead cells, while vitamin E inhibited these effects. Neither of these events was observed at any significant level in Sk cells. Identity of PUFA-OHs was confirmed by determining the regional positions of the hydroxyl group by GC-MS analysis of hydrogenated methyl ester tert-butyldimethylsilyl ether alcohol derivatives (Me-H2-PUFA-O-TBDMS). The regional isomers identified were 15-, 12- and 8-OH 20 carbon and 13-OH 18 carbon fatty acid derivatives. These results suggest that the increased formation of conjugated dienes and/or hydroperoxyl (or peroxyl) groups in PUFA molecules is relevant to the cancer cell-killing effect of GLA+Fe.
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PMID:Mechanism of lipid peroxidation in cancer cells in response to gamma-linolenic acid (GLA) analyzed by GC-MS(I): Conjugated dienes with peroxyl (or hydroperoxyl) groups and cell-killing effects. 838 94

Several studies suggest that work in electrical occupations is associated with an increased risk of cancer, mainly leukaemia and brain tumours. These studies may, however, not be representative if there is a publication bias where mainly positive results are reported. To study an unselected population the incidence of cancer was followed up over a 17 year period (1970-87) in a cohort of 2.8 million Danes aged 20-64 years in 1970. Each person was classified by his or her industry and occupation in 1970. Before tabulation of the data on incidence of cancer, each industry-occupation group was coded for potential exposure to magnetic fields above the threshold 0.3 microT. Some 154,000 men were considered intermittently exposed and 18,000 continuously exposed. The numbers for women were 79,000 and 4000 respectively. Intermittent exposure was not associated with an increased risk of leukaemia, brain tumours, or melanoma. Men with continuous exposure, however, had an excess risk of leukaemia (observed (obs) 39, expected (exp) 23.80, obs/exp 1.64, 95% CI 1.20-2.24) with equal contributions from acute and other leukaemias. These men had no excess risk of brain tumours or melanoma. A risk for breast cancer was suggested in exposed men but not in women. The risk for leukaemia in continuously exposed men was mainly in electricians in installation works and iron foundry workers. Besides electromagnetic fields other exposures should be considered as possible aetiological agents.
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PMID:Incidence of cancer in persons with occupational exposure to electromagnetic fields in Denmark. 839 64

The decay of nitroxide spin label electron paramagnetic resonance (EPR) absorption intensity was used to investigate the doxorubicin-mediated intracellular generation of free radicals. The effects of 50-500 micrograms/ml doxorubicin on human tumor cells (MCF-7, breast cancer cells, and HL-60, promyelocytic leukemia, cells) were studied by measuring 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) absorption intensity decay (TAID) at a TEMPO concentration of 10 microM. Doxorubicin accelerated the TAID in both cell lines with a detection limit of 50 micrograms/ml for MCF-7 cells and 500 micrograms/ml doxorubicin for HL-60 cells. Preincubation of cells with the iron chelating agent, deferoxamine (5 mM), partially prevented the effects of doxorubicin on the TAID. Catalase and copper, zinc-superoxide dismutase (Cu,Zn-SOD) had no influence on the effects of doxorubicin on the TAID in intact cells. However, Cu,Zn-SOD completely abolished the effects of doxorubicin on the TAID in a MCF-7 cell-free system. Our findings suggest that doxorubicin mediates the intracellular generation of O2.- and that iron is involved in this process.
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PMID:Doxorubicin-mediated free radical generation in intact human tumor cells enhances nitroxide electron paramagnetic resonance absorption intensity decay. 841 98

Iron chelating agents have been demonstrated to inhibit tumour cell growth. However, in vitro and in vivo results using desferrioxamine a hexadentate iron chelating agent, for anti-cancer treatment are not always in agreement. Therefore, we have studied the response of three human tumour cell lines (HL-60 promyelocytic leukaemia, MCF-7 breast cancer and HepG2 hepatoma), grown in culture medium supplemented with either human pooled (HPS) or fetal bovine serum (FBS), to desferrioxamine. Desferrioxamine, at micromolar concentrations, induced severe cytotoxicity in all tumour cell lines grown in FBS medium. When grown in HPS medium, comparable desferrioxamine cytotoxicity was observed in the millimolar range. The addition of 50% saturated human transferrin to FBS medium resulted in protection against desferrioxamine cytotoxicity. HL-60 cells were further studied for iron metabolism characteristics. HL-60 cells, grown in medium with FBS, were found to have an 8.4 fold increase in surface transferrin receptor (TfR) expression (P < 0.001) as compared with HL-60 cells grown in medium with HPS. However, iron uptake of HPS cultured HL-60 cells, after incubation with saturated human transferrin, was higher, resulting in a higher concentration of iron in HPS cultured HL-60 cells as compared with FBS cultured cells (1.72 +/- 0.02 mumol/g protein v. 1.32 +/- 0.14 mumol/g protein; P < 0.001). Using desferrioxamine it was shown that TfR expression is dependent on the biological availability of iron in the cell. Consistent with the lower iron content in FBS cultured cells, we conclude that the cytotoxicity of desferrioxamine is dependent on the ability of cells to replenish cellular iron stores from the culture medium. Cells grown in FBS medium lack this ability and are therefore more susceptible to desferrioxamine.
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PMID:The in vitro response of human tumour cells to desferrioxamine is growth medium dependent. 843 91

The transferrin receptor is expressed on the surface of rapidly dividing cells that require iron as a co-factor for essential redox reactions and deoxyribonucleotide synthesis. Transferrin receptors are expressed on the surface of breast carcinoma cells but not on benign breast tumor cells. In this study, the authors investigated whether transferrin receptor concentrations in the serum were elevated in patients with invasive adenocarcinoma of the breast. The transferrin receptor was isolated and purified from human placenta by affinity chromatography. The serum transferrin receptor concentration was determined using an enzyme-linked immunosorbent assay in 19 patients with invasive breast adenocarcinoma, 12 of whom had involvement of axillary lymph nodes. These results were compared with those from 16 normal age-matched female controls. In the invasive breast cancer group, the range of transferrin receptor concentrations was 2.60-7.34 mg/L (mean, 4.44 mg/L) compared with 2.85-8.80 mg/L (mean, 5.49 mg/L) in the control group. Nine patients with in situ adenocarcinoma of the breast had transferrin receptor concentrations of 3.68-6.66 mg/L (mean, 4.94 mg/L). For both the invasive carcinoma group and the in situ group, the means were not significantly different from those of the control group (P = 0.06 and 0.32, respectively). It was concluded that the differential expression of transferrin receptor on the surface of malignant tumor cells in adenocarcinoma of the breast was not reflected by changes in circulating transferrin receptor concentrations.
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PMID:Serum transferrin receptor level is not altered in invasive adenocarcinoma of the breast. 844 82

To investigate the relation between selected micronutrients and breast cancer risk, we conducted a case-control study of breast cancer between June 1991 and April 1994 in 6 Italian areas. The study included 2569 women admitted to the major teaching and general hospitals of the study areas with histologically confirmed incident breast cancer and 2588 control women with no history of cancer, who were admitted to hospitals in the same catchment areas for acute, non-neoplastic, nongynecological conditions unrelated to hormonal or digestive tract diseases or to long-term modifications of the diet. Dietary habits, including alcoholic beverage consumption, were investigated using a validated food frequency questionnaire, including 78 foods or food groups, several types of alcoholic beverages, some "fat intake pattern" questions and some open sections for foods consumed frequently by the subject and not reported in the questionnaire. To control for potential confounding factors, several multiple logistic regression models were used. When major correlates, energy intake and the mutual confounding effect of the various micronutrients were taken into account, beta-carotene, vitamin E and calcium showed a significant inverse association with breast cancer risk. The estimated odds ratios of the 5th quintile compared to the lowest one were 0.84 for beta-carotene, 0.75 for vitamin E and 0.81 for calcium. No significant association emerged for retinol, vitamin C, thiamin, riboflavin, iron and potassium. Our results suggest that a diet rich in several micronutrients, particularly beta-carotene, vitamin E and calcium, may be protective against breast cancer.
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PMID:Intake of selected micronutrients and the risk of breast cancer. 856 8

Previously, a panel of mouse monoclonal antibodies (mAbs) to several tumor-associated antigens was chemically crosslinked to an IgG1 anti-human transferrin receptor antibody, 454A12. We called this new class of bispecific antibodies (BmAbs) "antigen forks" and showed that these antigen forks inhibited but did not completely prevent tumor cell growth. We speculated that the conjugates acted by heterologously crosslinking two antigens in a manner that interfered with the functions of one or both. The most effective BmAbs all shared one specificity for the human transferrin receptor. A monoclonal antibody to this receptor has been shown by others to reduce tumor cell growth when used with the iron chelator deferoxamine. When we combined our antigen forks with deferoxamine, two of five BmAbs synergized with deferoxamine to arrest tumor cell count at or below input levels. The most effective BmAbs were 317G5/454A12 (3/4) and 520C9/454A12 (5/4). mAb 317G5 recognizes a 42-kDa tumor-associated glycoprotein, and mAb 520C9 recognizes the c-erbB-2 protooncogene product. BmAb 3/4 was most effective against colorectal cancer cell line HT-29, and BmAb 5/4 was most effective against breast cancer cell line SK-BR-3. When deferoxamine and BmAb were replaced by fresh medium after a 6- or 7-day treatment period, no regrowth of tumor cells was observed during the next 4 days, although regrowth was seen if either deferoxamine or BmAb was used alone. Our results show that BmAbs with specificities for transferrin receptor and certain tumor-associated antigens effectively inhibit tumor growth in vitro. When used in combination with deferoxamine, such BmAbs may have therapeutic potential for the treatment of cancer.
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PMID:In vitro tumor growth inhibition by bispecific antibodies to human transferrin receptor and tumor-associated antigens is augmented by the iron chelator deferoxamine. 876 64


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