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)

The possibility that appropriately designed chemotherapy could act selectively against p53-defective tumor cells was explored in MCF-7 human breast cancer cells. These cells were chosen because they have normal p53 function but are representative of a tumor cell type that does not readily undergo p53-dependent apoptosis. Two sublines (MCF-7/E6 and MCF-7/mu-p53) were established in which p53 function was disrupted by transfection with either the human papillomavirus type-16 E6 gene or a dominant-negative mutant p53 gene. p53 function in MCF-7/E6 and MCF-7/mu-p53 cells was defective relative to control cells in that there were no increases in p53 or p21Waf1/Cip1 protein levels and no G1 arrest following exposure to ionizing radiation. Survival assays showed that p53 disruption sensitized MCF-7 cells to cisplatin (CDDP) but not to several other DNA-damaging agents. CDDP sensitization was not limited to MCF-7 cells since p53 disruption in human colon carcinoma RKO cells also enhanced sensitivity to CDDP. Contrary to the other DNA-damaging agents tested, CDDP-induced DNA lesions are repaired extensively by nucleotide excision, and in agreement with a defect in this process, MCF-7/E6 and MCF-7/mu-p53 cells exhibited a reduced ability to repair a CDDP-damaged chloramphenicol acetyltransferase-reporter plasmid transfected into the cells. Therefore, we attributed the increased CDDP sensitivity of MCF-7 cells with disrupted p53 to defects in G1 checkpoint control, nucleotide excision repair, or both. The G2 checkpoint inhibitor pentoxifylline exhibited synergism with CDDP in killing MCF-7/E6 cells but did not affect sensitivity of the control cells. Moreover, pentoxifylline inhibited G2 checkpoint function to a greater extent in MCF-7/E6 than in the parental cells. These results suggested that, in the absence of p53 function, cancer cells are more vulnerable to G2 checkpoint abrogators. Our results show that a combination of CDDP and pentoxifylline is capable of synergistic and preferential killing of p53-defective tumor cells that do not readily undergo apoptosis.
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PMID:Disruption of p53 function sensitizes breast cancer MCF-7 cells to cisplatin and pentoxifylline. 771 69

Digital image analysis provides objective measurements of tissue and cell analytes previously interpreted subjectively. Both analyte concentration determination and morphometric analyses are possible. Calibration of the instrument and the use of standards and controls are essential for precise and reproducible quantitation of the analyte. Multi-tissue blocks ensure reproducible staining of the batch in quantitative immunohistochemical assays such as breast cancer estrogen and progesterone receptors. These multi-tissue blocks can be shared among laboratories to reduce interlaboratory variation and to objectively quantitate estrogen and progesterone receptors in clinical trials. In colon carcinoma, p53 can be quantitated objectively by image analysis. In prostate carcinoma, morphometric analysis of nuclear shape, nuclear roundness factor, and variations in nuclear size are objective measurements which constitute the pathologist's nuclear grade. Developments in instrumentation have now made it possible to combine analyte determination (such as DNA ploidy) and morphologic analysis of tumors, a diagnostic improvement over either method alone. A study employing image analysis to detect and quantitate androgen receptors and p53 in formalin-fixed, paraffin-embedded prostate cancer biopsies is underway to determine the utility of androgen receptors in predicting response to hormonal therapy. Histopathological features such as nuclear size, shape, and pleomorphism must be converted to image features such as area, shape factor, and variance of the area; this feature vector must be correlated with the pathologist's expert opinion or diagnosis. Other applications of image analysis include quantitation of immunofluorescent assays such as anti-nuclear antigen or anti-cytoplasmic nuclear antigen. Fluorescent image analysis provides more precision and greater reproducibility, as well as reduced test costs.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Quantitation and morphometric analysis of tumors by image analysis. 782 83

1,25-(OH)2-Vitamin D3, the active metabolite of vitamin D, is a secosteroid hormone with known differentiating activity in leukemic cells. Studies have demonstrated the presence of vitamin D receptors (VDR) in a wide range of tissues and cell types. Antiproliferative activity of 1,25-(OH)2-vitamin D3 has been documented in osteosarcoma, melanoma, colon carcinoma, and breast carcinoma cells. This study was designed to analyze vitamin D receptor level in breast cancer cells as a marker of differentiation and as a predictor of growth inhibition by 1,25-(OH)2-vitamin D3. VDR messenger RNA was found to be present in relatively high levels in well-differentiated cells and in low levels in poorly differentiated cells. All cell lines had detectable VDR mRNA. Radiolabeled ligand binding assay showed a similar pattern. MCF-7 and T47D cells, which express VDR at moderate levels, showed significant growth inhibition by 10(-9) M1,25-(OH)2-vitamin D3 (p < 0.05). MDA-MB-231 cells, which have very low levels of VDR, demonstrated no growth inhibition by 1,25-(OH)2-vitamin D3 at concentrations up to 10(-6) M. Based on these results it can be stated that VDR expression is lost with de-differentiation and that receptor is essential for the antiproliferative response to 1,25-(OH)2-vitamin D3.
Breast Cancer Res Treat 1994
PMID:Vitamin D receptors in breast cancer cells. 788 Oct 99

The human and mouse cripto-1 (CR-1) genes can code for proteins related in structure to epidermal growth factor (EGF). A specific 36-kDa immunoreactive protein was detected by Western blot analysis in human cell lines that express CR-1 mRNA but not in cell lines that fail to express this transcript. Immunoprecipitation of GEO colon carcinoma or mouse embryonal carcinoma cells detected 27-29-kDa and 24-kDa proteins, respectively. Cell lysates and conditioned medium that were prepared from several CHO clones and were expressing either a recombinant human or mouse CR-1 cDNA contained immunospecific 27-29-kDa and 24-kDa proteins, respectively. Monensin or tunicamycin treatment resulted in a shift of the 27-29-kDa human CR-1 protein to 24 kDa and 20 kDa, respectively. The 20-kDa protein was also observed after digestion of the 27-29-kDa human CR-1 protein with N-glycosidase F. Using two CR-1 synthetic refolded peptides that correspond to the EGF-like domain of the human CR-1 sequence or conditioned medium obtained from human CR-1 expressing CHO cells, growth stimulatory activity could be detected on non-transformed human mammary epithelial cells and on two human breast cancer cell lines. EGF receptor-blocking antibody did not inhibit the growth stimulatory action of the CR-1 protein. Likewise, the CR-1 refolded peptides or conditioned medium from the human CR-1-expressing CHO cells failed to inhibit the binding of 125I-EGF in an EGF-radioreceptor assay. These data demonstrate that the CR-1 is a glycoprotein that can function as a growth factor through an EGF receptor-independent pathway.
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PMID:Identification and biological characterization of an epidermal growth factor-related protein: cripto-1. 800 41

Primary chemotherapy is an established treatment in selected patients with osteosarcoma and locally advanced breast cancer. In several other tumor entities this therapeutic approach is under clinical investigation. In contrast, colon carcinoma has been believed to be chemoresistant for a long period of time. Thus, no therapeutic approaches dealing with preoperative therapy have been initiated yet. Recent studies showing remission rates as high as 40% in advanced colon cancer and the proof of efficacy for postoperative adjuvant chemotherapy must now lead to reevaluation of the therapeutic approach to this tumor entity. Data from animal models as well as several tumor biologic hypotheses also point to a possible advantage for preoperative therapy in order to ameliorate relapse-free survival and overall survival in these patients. In this work we discuss potential advantages and disadvantages of primary, neoadjuvant strategies of treatment for colon cancer. Based on these pros and cons, clinical studies for a preoperative therapeutic approach appear to be justified and necessary in patients with locally advanced disease and in patients with metastases at the time of diagnosis.
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PMID:[Primary (preoperative, neoadjuvant) chemotherapy of colon cancer--a therapeutic alternative?]. 808 4

Thymidylate synthase (TS; EC 2.1.1.45) is an important therapeutic target for fluoropyrimidine cytotoxic drugs that are widely used for the treatment of solid tumors. Using the monoclonal antibody TS 106, we have developed an ultrasensitive enzyme-linked immunoassay (ELISA) for the detection and quantitation of TS. Using a chemiluminescent ELISA technique, TS was detectable in serially diluted lysates from NCI H630 and HCT 116 human colon carcinoma cell lines. The ELISA assay was reliably able to detect activity down to a level of 30 attamol of TS protein above background (P2 = 0.016). The usable range of detection was from 0.03 to 500 fmol of enzyme. There was a close correlation between the optical density signal and the total TS enzyme between both cell lines (r2 = 0.96). The ELISA was used to measure TS in cytosolic extracts from human tumor samples, and it was able to quantitate TS levels using as little as 1-mg tumor biopsy samples. The mean total TS measured by ELISA in seven tumor samples from patients with breast cancer and sarcomas was 131 fmol/mg cytosolic protein (range 60-240) compared with a mean TS of 85 fmol/mg cytosolic protein (range 35-163) using the fluorodeoxyuridine monophosphate binding assay. While the TS levels were uniformly higher when measured by ELISA, there was close proportional agreement between both assays (r2 = 0.84). Thus, the chemiluminescent TS ELISA would appear to be an extremely sensitive and specific assay that may be used to quantitate TS in tumor tissue specimens.
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PMID:Quantitation of thymidylate synthase in human tumors using an ultrasensitive enzyme-linked immunoassay. 832 86

Replication errors at microsatellite repeats are markers for genomic instability in hereditary nonpolyposis colon carcinoma and in some sporadic cancers. Microsatellite sequences may show alterations in one or both alleles in some tumors, suggesting an error in the DNA replication of dinucleotide repeats. We have investigated microsatellite instability (MSI) in sporadic breast tumors at several loci on the short arm of chromosome 11. Among microsatellites studied we found a high frequency of MSI at one specific locus, D11S988 on chromosome 11p15.5. Most colorectal tumors that exhibit MSI display abnormalities of at least one other locus and usually more. By contrast we have detected only one abnormal microsatellite in all the tumors examined. This marker lies between the TH and HBB genes, a subregion previously suggested to harbor a putative tumor suppressor gene for breast cancer. Loss of heterozygosity for chromosome markers at 11p15 has earlier been correlated with poor prognosis. In an unselected panel of primary breast tumors, we observed that 20 of 69 showed mobility shifts of D11S988 in tumor compared with corresponding normal DNA samples. Tumors with instability at D11S988 were rapidly proliferating compared with tumors without MSI. DNA aneuploidy, estrogen receptor positivity and moderate to poorly differentiated tumor phenotype were also characteristics of tumors with MSI at this locus and the majority also exhibited loss of heterozygosity at one or more of the six 11p loci analyzed. Taken together these data suggest that MSI at the D11S988 locus is a late event in mammary tumorigenesis and may be associated with progression of breast carcinomas.
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PMID:Microsatellite instability at a single locus (D11S988) on chromosome 11p15.5 as a late event in mammary tumorigenesis. 859 12

The impact of prognostic markers on disease-free and overall survival reflects their relative role in tumour biology. Breast cancer and colon carcinoma can be taken as examples to demonstrate the clinical and biological relevance of 'new markers' of neoplastic disease. In breast cancer, receptor-bound urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 seem to play an important role in the dissolution of the surrounding tissue and the formation of tumour stroma. These processes are prerequisites for invasion and metastasis. The study of 'classical' and 'new' prognostic factors showed that uPA and PAI-1 content of breast cancer tissue are strong and independent prognostic factors. Also in colorectal cancer the prognostic relevance of plasminogen activators and inhibitors was analysed. In particular, low tissue plasminogen activator (tPA) levels, as antigen or as activity, high uPA: tPA antigen ratio in corresponding normal mucosa, high levels of uPA-related antigen and activity and of PAI-2 antigen in neoplastic tissue, and high uPA (neoplastic mucosa): tPA (normal mucosa) ratio, were all parameters associated with a poor overall survival. In conclusion, all these observations show the clinical importance of plasminogen activators and inhibitors at tissue levels with respect to cancer development and survival of patients affected by breast carcinoma or colorectal neoplasia. These new prognostic markers will also permit a better patient selection for a possible adjuvant treatment.
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PMID:Fibrinolysis components as prognostic markers in breast cancer and colorectal carcinoma. 869 36

Seventy two patients presenting with symptomatic brain metastases from undiagnosed primary neoplasms were retrospectively reviewed. Primary malignancies were diagnosed before death in 54 patients and remained unknown in 18 patients. Lung cancer was the most common primary tumour (72%), followed by breast cancer, colon carcinoma, and melanoma. On physical examination, 51 patients had organ specific symptoms or signs providing guidelines to the diagnostic evaluation. In 24 of the 52 patients with a primary lung tumour, and in four of the 20 patients without, organ specific complaints or findings suggested this tumour type, resulting in a positive predictive value of 85%. Overall, radiography and CT of the chest were very useful in detection of primary lung tumours. This could partly be explained by the high prior probability of detecting such tumours. Other diagnostic procedures should be used on indication only. The prognosis of patients with confirmed primary tumour position did not differ from those with unidentified primary tumour.
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PMID:Brain metastases from an unknown primary tumour: which diagnostic procedures are indicated? 879 9

The development of recombinant vaccines for specific immunotherapy of carcinoma represents a novel approach for the treatment of breast cancer and other tumor types. This article reviews the various parameters that should be considered in the development of recombinant vaccines. Several breast cancer associated antigens are also discussed which may provide potential target molecules. The human carcinoembryonic antigen (CEA), which is expressed on approximately 50% of breast cancers, represents one such target for immunotherapy. To enhance the immunogenicity of this antigen, a recombinant CEA-vaccinia vaccine, designated rV-CEA, was produced. To study the effects of this vaccine in an animal model, a murine colon carcinoma cell line was transduced with CEA and transplanted into immunocompetent mice for protection and therapy studies. Pre-clinical toxicity studies were also conducted in non-human primates. The results of these studies showed the rV-CEA vaccine to be immunogenic and safe in both rodents and primates, and to elicit good anti-tumor responses in the rodent model. In a Phase I clinical trial in metastatic breast, lung, and colorectal cancer patients involving three immunizations of rV-CEA, at three dose levels, enhancement of T-cell and antibody responses to vaccinia virus proteins were observed with no toxicity. Specific T-cell responses were studied via stimulation of peripheral blood lymphocytes with specific peptide epitopes from the CEA molecule. These studies demonstrated clear cut differences in establishment of T-cell lines pre- versus post-immunization. The T-cell lines were shown to be CD8+ and/or CD4+/CD8+, to lyse EBV transformed B-cells transduced with the CEA gene, and to lyse CEA positive carcinoma cells in a HLA restricted manner. Thus, in a Phase I clinical trial the rV-CEA vaccine has been shown to stimulate a CTL response specific for CEA defined epitopes in cancer patients.
Breast Cancer Res Treat 1996
PMID:Strategies for the development of recombinant vaccines for the immunotherapy of breast cancer. 882 20


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