UMLS:C0006142 - FACTA Search

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

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

Development of multidrug resistance (MDR) in cancer cells decreases net doxorubicin (ADR) uptake as a result of increased efflux, increased intracellular sequestration, and decreased membrane permeability. In this study, we investigated whether conjugation of ADR to transferrin (Tf) could overcome MDR in breast cancer cells. The multidrug resistant MCF-7/ADR breast cancer cell line was over 1000-fold more resistant to ADR, than its parental MCF-7 cell line, as determined by 3[H]-thymidine assay. The MCF-7/ADR cell line also expressed both MDR1 and MRP genes, as detected by RT-PCR. The ADR was coupled using a glutaraldehyde technique to human transferrin saturated with either ferric chloride (Fe-Tf) or gallium nitrate (Ga-Tf). These conjugates were tested for cytotoxicity on both MCF-7 and MCF-7/ADR cells after 6 days of incubation. The doxorubicin-gallium-transferrin conjugate (ADR-Ga-Tf) exhibited approximately the same inhibitory effect as ADR on MCF-7 cells with IC50s of 2.34 x 10(-3) microM and 1.42 x 10(-3) microM, respectively. However in MCF-7/ADR cells ADR-Ga-Tf reversed resistance to free ADR and decreased 100-fold the IC50 from 8.98 microM with free ADR to 9.52 x 10(-2) microM. ADR-Fe-Tf was 10-fold more inhibitory to MCF-7/ADR cells than free ADR. Compared to Ga-Tf, ADR-Ga-Tf was 500- and 3000-fold more inhibitory to MCF-7 and MCF-7/ADR cells, respectively. These results demonstrated that ADR-Ga-Tf reverses resistance to free ADR and Ga-Tf in MCF-7/ADR cells. The distribution of ADR in both cell lines was examined by fluorescence microscopy. It was noted that ADR mainly accumulated in the cytoplasm around the nucleus in MCF-7/ADR cells, but in both the cytoplasm and nucleus of MCF-7 cells. However the conjugate of ADR-Ga-Tf allowed ADR to accumulate in the cytoplasm and nucleus of both the MCF-7/ADR and MCF-7 cells. Further investigation of MDR1 and MRP genes expression by RT-PCR demonstrated that Ga-Tf decreased expression of the MRP more than the MDR1 gene. Therefore the reversal of resistance to ADR by the ADR-Ga-Tf conjugate is mediated by the transferrin receptor transmembrane transport mechanism, redistribution of ADR into the nucleus of ADR resistant MCF-7/ADR cells and inhibition of MRP gene expression.
...
PMID:Doxorubicin-gallium-transferrin conjugate overcomes multidrug resistance: evidence for drug accumulation in the nucleus of drug resistant MCF-7/ADR cells. 1081 Mar 57

It is well known that iron plays an essential role in many biochemical reactions and that rapidly growing cells require more iron for their growth and metabolism than resting cells. Transferrin and its receptor are required for entry of iron into the cell. In contrast, ferritin is a cellular storage protein whose main function is to sequester excess ferric iron and thus prevent high concentrations of soluble ferric iron from becoming toxic to the cell. However, the clinical significance of both transferrin receptor and ferritin mRNA levels have not previously been described in tumors from breast cancer patients. In this study, tumor tissue mRNA levels of transferrin receptor and ferritin were quantitated on forty-two breast cancer patients. A highly sensitive non-radioisotopic cDNA polymerase chain reaction assay was used to quantitate expression of mRNA. The expression of glyceraldehyde-3-phosphate dehydrogenase served as the control. In the tumor tissue from the 42 breast cancer patients the transferrin receptor mRNA levels were significantly correlated to the ferritin H-chain mRNA levels (Spearman correlation r = 0.5433, p = 0.0002; Pearson correlation r = 0.6276, p < 0.0001). The level of amplified transferrin receptor complementary DNA was related to differentiation (ANOVA, p = 0.042) with poorly differentiated tumors having high levels of transferrin receptor mRNA. Further, the levels of amplified gene for ferritin heavy chain complementary DNA was directly related to axillary lymph nodes status (Student's t-test, p = 0.044), presence of metastatic disease (Student's t-test, p = 0.046) and clinical stage (stage I + stage II versus stage III + stage IV; Student's t-test, p = 0.0181). These results demonstrate that non-radioisotopic RT-PCR is a very sensitive method for determining mRNA levels in tumor tissue. Additionally, the quantitation of expression of transferrin receptor and ferritin heavy chain mRNA may be useful for assessing prognosis and guiding therapeutic decisions in breast cancer patients.
...
PMID:Expression of transferrin receptor and ferritin H-chain mRNA are associated with clinical and histopathological prognostic indicators in breast cancer. 1129 1

Transferrin receptor expression is controlled by the amount of iron required by the cell to maintain its metabolism and therefore tumor cells in a highly proliferative state have a high density of transferrin receptors. In this study, phosphorothioated antisense TfR oligonucleotides (TfR-ODna) targeted to the sequences of TfR mRNA including the AUG initiation codon and the control sense chain (TfR-ODns) were synthesized. The rate of cellular DNA synthesis was determined by [3H]-thymidine incorporation. Administering TfR-ODna to three morphologically distinct breast cancer cell lines (MCF-7, T47D, and MDA-MB-231) and a normal breast cell line (MCF-12A) caused specific inhibition of tumor cell growth. The IC50 (50% inhibition of DNA synthesis) of the TfR-ODna for the MCF-7, T47D and MDA-MB-231 cells were 0.5, 0.5, and 1.0 microM, respectively, whereas the MCF-12A normal breast cells were about 30 times (IC50 of 30 microM) less sensitive to TfR-ODna than the breast cancer cells. The cytotoxicity of the antisense TfR-ODna was 10 to 60 times greater than that of the sense chain (TfR-ODns). TfR mRNA and protein synthesis were demonstrated by RT-PCR and immunohistochemical staining, respectively. Approximately 50% inhibition of the expression of TfR mRNA was observed when breast cancer cells were treated with 1 microM antisense TfR ODNa for 72 hrs but 1 microM antisense only caused 14% inhibition in normal breast cells. The decreased cytotoxicity and inhibition of TfR gene expression when the tumor cells were treated with the same concentration (1 microM) of TfR-ODns demonstrated the specificity of the TfR-ODna for blocking the target TfR gene. The combined cytotoxicities to human breast tumor MCF-7 cells of the antisense TfR-ODna and the iron chelator deferoxamine (DFO) or the ribonucleotide reductase inhibitor hydroxyurea were observed in this study. IC50s (50% inhibition of DNA synthesis) for DFO and hydroxyurea individually were 0.3 microM and 250 microM, respectively. The CalcuSyn program was used to determine the combined effects among the agents and synergism (Combined Indexes (CI) < 1) were found with the following two combinations: TfR-ODna (0.007 microM to 0.15 microM) with DFO (0.15 microM to 5 microM) and TfR-ODna (0.007 microM to 0.15 microM) with hydroxyurea (50 microM to 800 microM). However, inhibition by TfR-ODns was not synergistic with either DFO or hydroxyurea. The synergistic effects on inhibition of DNA synthesis between TfR-ODna and DFO or hydroxyurea suggest that inhibition of breast cancer cell growth by TfR-ODna is produced by depletion of iron pools that are required for DNA synthesis in tumor cells. The fact that TfR-ODna specifically decreases cell viability and proliferation, and reduces TfR mRNA and protein expression in human breast carcinoma cells without affecting normal breast cells, suggests that the antisense oligonucleotide to the transferrin receptor may be a novel therapeutic approach in breast cancer.
...
PMID:Inhibition of growth of human breast carcinoma cells by an antisense oligonucleotide targeted to the transferrin receptor gene. 1149 59

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) has been widely used after autologous peripheral blood stem cell transplant (APBSCT) in an attempt to reduce the duration of neutropenia, but whether this treatment has any influence on long-term engraftment remains unknown. We have retrospectively analyzed data from breast cancer patients to compare post-APBSCT rhG-CSF administration in terms of the short-term benefit and myeloid marrow regeneration after 1 year. Group A included 10 patients not treated with post-APBSCT rhG-CSF, while groups B and C comprised 15 and 13 patients treated with this drug from days +1 and +6, respectively. No differences among the three groups were found in age, diagnosis, previous chemo-radiotherapy, CD34+/CD71- cell concentration in pre-transplant bone marrow (BM), mobilization schedule, CD34+ cell yield, conditioning regimen and post-transplant radiotherapy. Post-APBSCT rhG-CSF was shown to accelerate neutrophil recovery, but there were no significant differences in platelet recovery, transfusion requirements, days of fever, antibiotic administration or inhospital stay. With regard to BM hematopoietic precursors 1 year after APBSCT, significantly lower concentrations of total CD34+ cells, committed CD34+/CD33+ subsets, and more immature CD34+/CD71- cells were found in both groups B and C compared with patients not having received the cytokine (group A). Thus, post-APBSCT rhG-CSF administration does not appear to beneficially affect procedure outcome, and might even impair long-term marrow hematopoiesis.
...
PMID:Administration of post-autologous PBSCT rhG-CSF is associated with long-term low concentrations of bone marrow hematopoietic progenitor cells. 1154 47

The transferrin receptor is often highly expressed in tumor cells whereas it is usually present at low levels in surrounding normal adult tissue. Here, a potential anti-cancer agent is described, which is directed at this receptor and consists of a toxin-modified transferrin, which is activated via photodynamic therapy. The porphyrin chlorin e6 was conjugated to transferrin using a procedure, which involved the preliminary binding of the protein to quaternary amino ethyl-sephadex. This maintained the natural activity of the transferrin, and the un-activated conjugate exhibited no in vitro cellular toxicity. The conjugate's singlet oxygen yield was estimated by assessment of its light-dependent oxidation of tetramethylbenzidine, where it displayed approximately 70% of the efficiency of native chlorin e6. When chlorin e6-transferrin treated human MCF7 and rat MTLn3 mammary adenocarcinoma cells were exposed to toxin-activating visible light, a tumor cell killing effect was achieved in normal (medium plus 10% FBS) culture conditions with an ED50 of approximately 10-20 microg/ml. A method for the synthesis of chlorin e6-transferrin was developed, and the conjugate was shown to exhibit a light-dependent killing of mammary adenocarcinoma cells in culture. The conjugate demonstrated potential as an anti-cancer agent.
Breast Cancer Res Treat 2002 Mar
PMID:Synthesis of chlorin e6-transferrin and demonstration of its light-dependent in vitro breast cancer cell killing ability. 1203 2

Advances in molecular and cell biology have led to further understanding of the mechanisms of malignant growth and metastasis in human breast cancer cells. Initiation and progression of breast cancer results from mutations and the abnormal expression of many genes that control cellular proliferation, differentiation, invasion, metastasis and sensitivity to therapy (chemotherapy and radiation therapy). Inhibition of host immunity also plays a role in breast cancer progression. Many genes have been selected as targets for antisense therapy, including HER-2/neu, PKA, TGF-alpha, EGFR, TGF-beta, IGFIR, P12, MDM2, BRCA, Bcl-2, ER, VEGF, MDR, ferritin, transferrin receptor, IRE, C-fos, HSP27, C-myc, C-raf and metallothionein genes. The strategy behind antisense therapy is the development of specific therapeutic agents that aim to correct the mutations and abnormal expression of cellular genes in breast tumour cells by decreasing gene expression, inducing degradation of target mRNA and causing premature termination of transcription. Many in vitro and in vivo studies have investigated the therapeutic efficacy of oligonucleotides and antisense RNAs. These studies have demonstrated specific inhibition of tumour cell growth by antisense therapy and have shown synergistic inhibitory effects between antisense oligonucleotides or antisense RNA and conventional chemotherapeutic drugs used in the treatment of breast cancer. Antisense oligonucleotides have been modified to improve their ability to penetrate cells, bind to gene sequences and downregulate target gene function. Many delivery systems for antisense RNA and antisense oligonucleotides have been developed, including virus vectors (retrovirus, adenovirus and adeno-associate virus) and liposomes, to carry the antisense RNA or oligonucleotides through the cell membrane into the cytoplasm and nucleus of the tumour cells. However, in order to determine their feasibility antisense therapies need to be further investigated to determine their antitumour activity, pharmacokinetics and toxicity in breast cancer patients.
...
PMID:Gene targets of antisense therapies in breast cancer. 1222 74

An ideal therapeutic for cancer would be one that selectively targets to tumor cells, is nontoxic to normal cells, and that could be systemically delivered, thereby reaching metastases as well as primary tumor. Immunoliposomes directed by monoclonal antibody or its fragments are promising vehicles for tumor-targeted drug delivery. However, there is currently very limited data on gene delivery using these vehicles. We have recently described a cationic immunoliposome system directed by a lipid-tagged, single-chain antibody Fv fragment (scFv) against the human transferrin receptor (TfR) that shows promising efficacy for systemic p53 tumor suppressor gene therapy in a human breast cancer metastasis model. However, the extremely low yield of this lipid-tagged scFv limited further downstream development and studies. Here we report a different expression strategy for the anti-TfR scFv, which produces high levels of protein without any tags, and a different approach for complexing the targeting scFv to the liposomes. This approach entails covalently conjugating the scFv to the liposome via a cysteine at the 3'-end of the protein and a maleimide group on the liposome. Our results show that this conjugation does not impair the immunological activity or targeting ability of the scFv. The scFv-cys targets the cationic liposome-DNA complex (lipoplex) to tumor cells and enhances the transfection efficiencies both in vitro and in vivo in a variety of human tumor models. This scFv-immunoliposome can deliver the complexed gene systemically to tumors in vivo, where it is efficiently expressed. In comparison with the whole antibody or transferrin molecule itself, the scFv has a much smaller size for better penetration into solid tumors. It is also a recombinant protein rather than a blood product; thus, large scale production and strict quality control are feasible. This new approach provides a promising system for tumor-targeted gene delivery that may have potential for systemic gene therapy of various human cancers.
...
PMID:Systemic tumor-targeted gene delivery by anti-transferrin receptor scFv-immunoliposomes. 1248 50

It is known that the interruption of normal iron metabolism with chelators of iron, toxic metals, toxic metals bound to transferrin, or anti-transferrin receptor antibodies leads to significant inhibition of tumor cell growth in cell culture systems and animal models. In the present study, we found that iron depletion was produced by the iron chelator deferoxamine mesylate, the free toxic metals gallium or indium, and the toxic metals gallium or indium bound to transferrin in the MCF-7 human breast cancer cell line, and this induced the condensation and fragmentation of chromatin, and the formation of DNA fragments characteristic of apoptosis. The induction of apoptosis was quantitated with acridine orange and ethidium bromide staining of apoptotic cells, separation of fragmented DNA from radiolabeled cells, and in situ terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) assays. The apoptosis, caused by deferoxamine mesylate, and gallium or indium bound to transferrin in the MCF-7 cells, can be completely inhibited by excess ferric chloride or equimolar iron-loaded transferrin. Gallium-transferrin and indium-transferrin complexes induced more apoptosis than their respective salts in the MCF-7 cells. Deferoxamine mesylate induced a small increase in the endogenous expression of both the bcl-2 and bax genes in the MCF-7 cells and this can be prevented by ferric chloride. In the 13762NF rat mammary adenocarcinoma model, in situ TUNEL assays showed that the iron-deficiency following a low iron diet or intravenous injection of deferoxamine mesylate produced 5.32 +/- 3.90% and 6.46 +/- 3.58% of apoptotic cells, respectively, compared to 2.01 +/- 1.20% of apoptotic cells in the control rats maintained on a normal diet (p < 0.05 and p < 0.01, respectively, Student's t-test). This is the first report of iron depletion caused by a low iron diet or deferoxamine mesylate treatment inducing apoptosis in rats bearing the 13762NF marnmary adenocarcinoma.
...
PMID:Induction of apoptosis by iron depletion in the human breast cancer MCF-7 cell line and the 13762NF rat mammary adenocarcinoma in vivo. 1252 82

Breast cancer is one kind of multi-gene related malignancy. Overexpression of some oncogenes such as HER-2 (c-erbB-2, Neu), bcl-2/bcl-xL, protein kinase A (PKA), and transferrin receptor gene (TfR gene), etc significantly affect the prognosis of breast cancer. It was shown that specific suppression of the overexpressed genes above resulted in the improvement of the therapy of breast cancer. Antisense interference, one of useful tools for inhibiting the overexpression of specific oncogenes, was involved in the therapy of breast cancer in recent years. Data indicated that antisense oligonucleotides (ON) could inhibit specially the expression of the target genes on mRNA or protein levels in most of cases; some ON candidates showed encouraging therapeutic effects in vitro and in vivo on breast cancer cell lines or xenografts. Furthermore, the combination use of the antisense ON and normal chemotherapeutic agents indicated synergistic antitumor effects, which was probably the best utilization of antisense ON in the treatment of breast cancer.
...
PMID:Advancements of antisense oligonucleotides in treatment of breast cancer. 1267 65

Mouse mammary tumor virus (MMTV) is a betaretrovirus that infects rodent cells and uses mouse transferrin receptor 1 for cell entry. To characterize the interaction of MMTV with its receptor, we aligned the MMTV envelope surface (SU) protein with that of Friend murine leukemia virus (F-MLV) and identified a putative receptor-binding domain (RBD) that included a receptor binding sequence (RBS) of five amino acids and a heparin-binding domain (HBD). Mutation of the HBD reduced virus infectivity, and soluble heparan sulfate blocked infection of cells by wild-type pseudovirus. Interestingly, some but not all MMTV-like elements found in primary and cultured human breast cancer cell lines, termed h-MTVs, had sequence alterations in the putative RBS. Single substitution of one of the amino acids found in an h-MTV RBS variant in the RBD of MMTV, Phe(40) to Ser, did not alter species tropism but abolished both virus binding to cells and infectivity. Neutralizing anti-SU monoclonal antibodies also recognized a glutathione S-transferase fusion protein that contained the five-amino-acid RBS region from MMTV. The critical Phe(40) residue is located on a surface of the MMTV RBD model that is distant from and may be structurally more rigid than the region of F-MLV RBD that contains its critical binding site residues. This suggests that, in contrast to other murine retroviruses, binding to its receptor may result in few or no changes in MMTV envelope protein conformation.
...
PMID:Identification of the receptor binding domain of the mouse mammary tumor virus envelope protein. 1297 Apr 32

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>