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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 variations in the cytotoxic activities of cisplatin analogues could be a result of differences in the aqueous chemistry of the compounds was investigated. A series of structurally related mixed-amine dichloroplatinum complexes (cis-coordinated with amine and various diphenylmethylamines and 1,2-diphenylethylamines) was prepared and selected physicochemical properties of the new compounds were characterized. Cytotoxicity was determined in two human breast cancer cell lines (MDA-MB-231 and MCF-7) and one human ovarian cancer cell line (SK-OV-3) by means of a microtiter assay. There is no apparent relationship between the hydrophobicities of the compounds and their cytotoxic potencies. There is no evidence for an inverse relationship between the aqueous stability of the dichloroplatinum complexes and cytotoxic potency, as has been reported for nitrogen mustards and some nitrosoureas. The differences in cytotoxic activity cannot be explained by inter-compound variations in the area under the concentration-time curves (AUC) of the dichloroplatinum complexes in culture medium. Thus, it appears that the differences in the cytotoxic potencies of this series of cisplatin analogues are related to factors other than dissimilarities in these physiochemical properties. Nevertheless, a relationship was found between the AUC of a dichloroplatinum complex in medium and the efficacy of the compound in the MCF-7 cell line. However, the AUC-efficacy relationship does not always hold in the MDA-MB-231 and SK-OV-3 cell lines. In these cells, treatment with a "high" bolus dose of platinum complex over finite exposure times is often less cytotoxic than treatment with lower doses of the same compound but over a continuous exposure time, although the cells are subjected to the same AUC of dichloroplatinum complex.
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PMID:Relationships between the aqueous chemistry and the in vitro cytotoxic activities of mixed-amine cisplatin analogues. 163 17

The paper discusses the results of an epidemiologic case-control study dealing with the risk of development of acute nonlymphoblastic leukemia in patients treated with radio- or chemotherapy. Out of 165 patients with primary multiple metachronous tumors, primary Hodgkin's disease, lymphosarcoma and breast, ovarian and testicular cancer, 18 developed secondary acute nonlymphoblastic leukemia; in 13, the primary tumor had been Hodgkin's disease, in 4--breast cancer and in one--testicular cancer. Relative risk (RR) of acute nonlymphoblastic leukemia proved higher in patients who had undergone radiation (RR = 6.4) or chemotherapy (RR = 1.9). Combination of those two procedures carried a higher risk, too (RR = 5.9). Relative risk of acute nonlymphoblastic leukemia proved the highest in patients treated with adriamycin (11.3) and nitrogen mustard (9.9) and much lower for cyclophosphamide (RR = 1.5).
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PMID:[The risk of the occurrence of acute nonlymphoblastic leukemia in patients with malignant neoplasms undergoing radio- and chemotherapy]. 166 2

A three-dimensional molecular template has been generated for substrates of human debrisoquine 4-hydroxylase cytochrome P450 (CYP2D6). This template defines the stereochemical requirements for CYP2D6 substrates in terms of the volume occupied and positions of key atoms. The modelling was based on the X-ray crystallographic coordinates of the location of the attacked C5 atom of camphor in relation to the haem in cytochrome P450 cam. Interactive molecular graphics combined with energy calculations were used to identify allowed conformers to superpose known CYP2D6 substrates to yield a molecular template. This model takes into account the site of attack of the known substrates and the requirement for a protonated nitrogen atom to interact with an anion site of the protein. A nitrogen-anion distance of between 2.5 and 4.5 A was allowed for the interaction. The substrates modelled were cardiovascular drugs (debrisoquine, sparteine, guanoxan and perhexiline), beta-adrenergic blocking agents (bufuralol and propranolol), tricyclic anti-depressants (desipramine, amitriptyline and nortriptyline) and other miscellaneous compounds (phenformin, methoxy-amphetamine, codeine and dextromethorphan). The template generated in this manner was then used to determine the likelihood that certain other compounds were substrates for CYP2D6. A carcinogenic protein pyrolysate product, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), did not fit the template and is therefore unlikely to be activated by this enzyme. A potent carcinogen in tobacco smoke, 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), fitted the template but could not be modelled to form a favourable nitrogen-anion interaction. Experimental substrate competition studies also showed that NNK is unlikely to be a CYP2D6 substrate. It was also shown that the widely used drug for treatment of breast cancer, trans-1-(4-beta-dimethylaminoethoxyphenyl)-,2-diphenyl-1-ene (tamoxifen), did not fit the molecular template and is unlikely to be metabolized by CYP2D6. Coordinates of the template are available.
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PMID:A three-dimensional molecular template for substrates of human cytochrome P450 involved in debrisoquine 4-hydroxylation. 174 20

A retrospective study was performed on 109 human breast tumors stored in liquid nitrogen in order to assess the prognostic value of epidermal growth factor receptor (EGF-R) (median patient follow-up 5 years). A significant inverse relationship was observed between EGF-R and both estrogen (ER) and progesterone receptors (PR). Univariate analysis showed a trend towards a shorter metastasis-free survival both in the overall population and in node-negative patients with EGF-R positive tumors. Multivariate analysis of the overall population showed that lymph-node involvement and PR status were the only significant variables in predicting metastasis-free survival. However, in patients receiving no adjuvant treatment (hormone therapy or chemotherapy). EGF was the only significant variable in the multivariate Cox analysis. No c-erbB-1 amplification was detected in these tumors.
Breast Cancer Res Treat 1990 Dec
PMID:Epidermal growth factor receptors and prognosis in primary breast cancer. 209 96

A series of 90 patients with primary operable breast cancer and with up to 36 months of follow up were investigated for expression of epidermal growth factor receptor (EGFR) in their tumours by immunocytochemical staining with the monoclonal antibody EGFR 1. Tumour samples were snap frozen in liquid nitrogen immediately after resection and subsequently stained using a standard indirect immunocytochemical method. Tumour staining was assessed by two observers and scored on a four point scale (0-3). Thirteen (14%) tumours showed positive immunoreactivity. A strong correlation between distinct EGFR expression and short disease free interval was observed. Significant correlations were also shown with oestrogen and progesterone receptor expression and tumour nuclear size. No significant association was found with tumour size, lymph node stage, and histological grade. The association with disease free interval remained significant in multivariate analysis.
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PMID:Expression of epidermal growth factor receptor in breast carcinoma. 237 Mar 6

Ischemia may invalidate hormone-receptor analyses. This study determined the effects of progressive ischemia on steroid hormone-receptor analyses. Breast cancer was induced in 50- to 60-day-old female Holtzman rats by intragastric administration of 25 mg of 7,12-dimethylbenz[a]anthracene. After 90 days, rats were anesthetized and breast tumors were devascularized in vivo. At 0, 30, 60, 90 and 150 minutes, a biopsy specimen from each tumor was taken and rapidly frozen. Steroid binding capacity for estrogen (ER), progesterone (PR), and androgen (AR) receptors was determined by incubation with tracer receptor ligand. Ischemia decreased ER and AR levels by 30 minutes, whereas PR levels were unchanged through 150 minutes of ischemia. Following mastectomy, tylectomy, or breast biopsy, PR may be the most reliable of the hormone receptors for determining endocrine-responsive breast cancer. However, for accurate determination of all hormone receptors, specimens should be frozen in liquid nitrogen immediately, then preserved at -70 degrees C, or processed immediately.
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PMID:Lability of steroid hormone receptors following devascularization of breast tumors. 253 31

The nitrogen mustard derivatives of 4-phenylbutyric acid and L-phenylalanine, called chlorambucil (Chl) and melphalan (Mel), respectively, have been incorporated into several peptide hormones, including luteinizing hormone-releasing hormone (LH-RH). The alkylating analogues of LH-RH were prepared by linking Chl, as an N-acyl moiety, to the complete amino acid sequence of agonistic and antagonistic analogues. These compounds, in particular the antagonistic analogues, showed much lower potency than their congeners carrying other acyl groups. To obtain highly potent alkylating analogues of LH-RH, the D enantiomer of Mel was incorporated into position 6 of the native hormone and some of its antagonistic analogues. Of the peptides prepared, [D-Mel6]LH-RH (SB-05) and [Ac-D-Nal(2)1,D-Phe(pCl)2,D-Pal(3)3,Arg5,D-Mel6,D-Ala10++ +]LH-RH [SB-86, where Nal(2) is 3-(2-naphthyl)alanine and Pal(3) is 3-(3-pyridyl)alanine] possessed the expected high agonistic and antagonistic activities, respectively, and also showed high affinities for the membrane receptors of rat pituitary cells, human breast cancer cells, human prostate cancer cells, and rat Dunning R-3327 prostate tumor cells. These two analogues exerted cytotoxic effects on human and rat mammary cancer cells in vitro. Thus these two D-Mel6 analogues seem to be particularly suitable for the study of how alkylating analogues of LH-RH could interfere with intracellular events in certain cancer cells.
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PMID:Highly potent analogues of luteinizing hormone-releasing hormone containing D-phenylalanine nitrogen mustard in position 6. 254 7

Phenothiazines and structurally related compounds inhibit cellular proliferation and sensitize multidrug-resistant (MDR) cells to chemotherapeutic agents. To identify more potent pharmaceuticals, we studied the structure-activity relationships of 30 phenothiazines and related compounds on cellular proliferation and MDR in sensitive MCF-7 and resistant MCF-7/DOX human breast cancer cells. Substitutions on the phenothiazine ring that increased hydrophobicity increased antiproliferative and anti-MDR activities. For example, -Cl and -CF3 groups increased whereas -OH groups decreased potency. Modifying the length of the alkyl bridge and the type of amino side chain also influenced potency. Compounds with increased activity against cellular proliferation and MDR possessed a four-carbon bridge rather than a three- or two-carbon bridge and a piperazinyl amine rather than a noncyclic amino group. Compounds with tertiary amines were better anti-MDR agents than those with secondary or primary amines but were equipotent antiproliferative agents. The effects of these substituents were unrelated to hydrophobicity. The structure-activity relationships suggest that an ideal phenothiazine structure for reversing MDR has a hydrophobic nucleus with a -CF3 ring substitution at position 2, connected by a four-carbon alkyl bridge to a para-methyl-substituted piperazinyl amine. We subsequently studied related compounds having certain of these properties. Substitution of a carbon for a nitrogen at position 10 of the tricyclic ring, with a double bond to the side chain (thioxanthene), further increased activity against MDR. For example, (trans)-flupenthixol, the most potent of these compounds, increased the potency of doxorubicin against MDR cells by 15-fold, as compared with its stereoisomer (cis)-flupenthixol (5-fold) or its phenothiazine homolog fluphenazine (3-fold). (cis)- and (trans)-flupenthixol were equipotent antiproliferative agents. (trans)-flupenthixol was not accumulated more than (cis)-flupenthixol in MDR cells, implying that their stereospecific anti-MDR effects were not the result of selective differences in the access of the drugs to intracellular targets. Both drugs increased the accumulation of doxorubicin in MDR cells, but not in sensitive cells, suggesting that they modulate MDR by interacting with a uniquely overexpressed cellular target in these resistant cells. The apparent lack of clinical toxicity of (trans)-flupenthixol makes it an attractive drug for further investigation.
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PMID:Structural features determining activity of phenothiazines and related drugs for inhibition of cell growth and reversal of multidrug resistance. 256 2

Platelets contain mitogenic activities for MCF-7 human breast cancer cells when assayed under serum-free chemically defined conditions. Purification from outdated human platelets identified insulinlike growth factor I (IGF-I) as the most potent breast cancer cell mitogen in lysates (Karey KP, Sirbasku DA: see accompanying article, this issue). In this study the release and subcellular localization of IGF-I was investigated. Degranulation of platelets by thrombin treatment caused release of lysosomal enzymes (beta-glucuronidase and N-acetyl-D-glucosaminidase), alpha-granule proteins (beta-thromboglobulin and fibrinogen) as well as mitogenic activity for MCF-7 cells and IGF-I as measured by radioimmunoassay (RIA) and radioreceptor assay. Release of mitogenic activity and immunologically identified IGF-I was induced tenfold over controls by thrombin and was nearly complete as compared to platelets disrupted by repeated freezing and thawing. Disruption of platelets by nitrogen cavitation followed by separation of the organelles by sucrose density gradient sedimentation showed that IGF-I and mitogenic activity localized predominantly to fractions containing alpha-granules rather than soluble cellular components, lysosomes, or dense granules. The morphology of MCF-7 cells in serum-free medium supplemented with supernatants from thrombin-treated platelets also indicated the release of important cell-adhesion factors for human breast cancer cells.
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PMID:Human platelet-derived mitogens. II. Subcellular localization of insulinlike growth factor I to the alpha-granule and release in response to thrombin. 275 54

Twelve patients with disseminated breast cancer were injected with monoclonal antibody MBr1 at the National Cancer Institute of Milan, Italy, from January 1983 to March 1985. The first seven patients had advanced disease and the remaining five operable breast cancer. In the first seven patients the initial dosage of MBr1 was 0.5 mg and was doubled in the next patient up to 16 mg. The last five women received 10 mg of MBr1. No general side effects such as bronchospasm, hypotension, immediate or delayed allergic reactions were observed. Four patients who were injected with 10 mg or more experienced fever, shudder and vague abdominal and articular pain. The following tests were monitored: R.B.C., W.B.C., percentage of lymphocytes, blood glucose, urea nitrogen and creatinine, serum levels of Na+, K+, Cl-, total proteins levels, albumins and globulins, bilirubin, GOT, GPT, alkaline phosphatase, LDH, amylase, gamma GT and CPK. No major modifications were observed: a limited increase of the transaminases, LDH and gamma GT was evident at the last check. An early temporary alteration of CPK was observed in the four patients who had symptoms. Serum levels of MBr1 are detectable immediately after injection starting from 4 mg, and all sera were negative 48 hours later. It is concluded that the scanty toxicity allows to continue clinical investigations to verify the linkage between MBr1 and Ca-MBr1 "in vivo" after a single injection of no more than 16 mg of the MoAb. The increase of this dosage as well as multiple injections do not seem safe at present.
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PMID:Evaluation of toxic effects following administration of monoclonal antibody MBr1 in patients with breast cancer. 287 47


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