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1.
Frankel LB Lykkesfeldt AE Hansen JB Stenvang J 《Breast cancer research and treatment》2007,104(2):165-179
Development of resistance to antiestrogen treatment in breast cancer patients is a serious therapeutic problem. The molecular
mechanisms contributing to resistance are currently unclear; however it is known that increased activation of growth signaling
pathways is involved. Protein Kinase C α (PKCα) is associated with a diverse range of cancers and is previously shown to be overexpressed in three out of four antiestrogen
resistant breast cancer cell lines. In this study we investigated whether PKCα contributes to antiestrogen resistant growth. A panel of nine resistant cell lines was investigated, all of which displayed
elevated levels of PKCα expression relative to parental MCF-7 cells. Stable PKCα overexpression in MCF-7 cells significantly reduced sensitivity to the antiestrogens, tamoxifen and ICI 182,780. Two resistant
cell lines were chosen for further studies: tamoxifen resistant MCF-7/TAMR-1 (TAMR-1) and ICI 182,780 resistant MCF-7/182R-6 (182R-6). Treatment with the PKCα inhibitor Ro-32–0432 resulted in a preferential growth inhibition of these two cell lines relative to MCF-7 cells. Moreover,
transient down-regulation of PKCα resulted in a 30–40% growth inhibition of TAMR-1 and 182R-6, while MCF-7 remained unaffected. Stable PKCα knock-down in TAMR-1 using small hairpin RNA, resulted in a tamoxifen sensitive “MCF-7–like” growth phenotype, while the same approach in 182R-6 cells did not alter their sensitivity to ICI 182,780. These results demonstrate a functional contribution of PKCα to tamoxifen resistant growth. Furthermore, our data suggest the potential for PKCα as a marker for antiestrogen resistance and as a promising therapeutic target in the treatment of tamoxifen resistant breast
cancer. 相似文献
2.
Elola MT Capurro MI Barrio MM Coombs PJ Taylor ME Drickamer K Mordoh J 《Breast cancer research and treatment》2007,101(2):161-174
Lewis x (Lex, CD15), also known as SSEA-1 (stage specific embryonic antigen-1), is a trisaccharide with the structure Galβ(1–4)Fucα(1–3)GlcNAc,
which is expressed on glycoconjugates in human polymorphonuclear granulocytes and various tumors such as colon and breast
carcinoma. We have investigated the role of Lex in the adhesion of MCF-7 human breast cancer cells and PMN to human umbilical endothelial cells (HUVEC) and the effects of
two different anti-Lex mAbs (FC-2.15 and MCS-1) on this adhesion. We also analyzed the cytolysis of Lex+-cells induced by anti-Lex mAbs and complement when cells were adhered to the endothelium, and the effect of these antibodies on HUVEC. The results
indicate that MCF-7 cells can bind to HUVEC, and that MCS-1 but not FC-2.15 mAb inhibit this interaction. Both mAbs can efficiently
lyse MCF-7 cells bound to HUVEC in the presence of complement without damaging endothelial cells. We also found a Lex-dependent PMN interaction with HUVEC. Although both anti-Lex mAbs lysed PMN in suspension and adhered to HUVEC, PMN aggregation was only induced by mAb FC-2.15. Blotting studies revealed
that the endothelial scavenger receptor C-type lectin (SRCL), which binds Lex-trisaccharide, interacts with specific glycoproteins of M
r␣∼␣28 kD and 10 kD from MCF-7 cells. The interaction between Lex+-cancer cells and vascular endothelium is a potential target for cancer treatment. 相似文献
3.
Philip J. Bergman Karen R. Gravitt C. A. O’Brian 《Cancer chemotherapy and pharmacology》1997,40(5):453-456
Protein kinase C-α (PKC-α) activation is an important contributing factor in human breast cancer MCF-7 MDR cell drug resistance.
We recently reported the use of N-myristoylated PKC-α pseudosubstrate peptides with potent PKC-α inhibitory activity as reversal agents of drug resistance in
MCF-7 MDR cells. The peptides potently inhibit phosphorylation of the PKC-α substrates P-glycoprotein (P-gp), raf kinase and
PKC-α itself in MCF-7 MDR cells in association with a severalfold induction of intracellular uptake of P-gp substrate chemotherapeutics
and a statistically significant twofold increase in cellular chemosensitivity. We now report that the N-myristoylated PKC-α pseudosubstrate peptide N-myristoyl-RFARKGALRQKNV (P3) is not a P-gp substrate in MCF-7 MDR cells based on a comparison of the cellular uptake of [125I]-radiolabeled P3 in MCF-7 MDR vs MCF-7 WT cells. The extent of cellular uptake of the radiolabeled peptide in the drug-resistant
cell line MCF-7 MDR was either greater than or equivalent to the uptake in the parental drug-sensitive MCF-7 WT cell line
over a time course of 30 min to 6 h, and across a peptide concentration range of 25 – 100 μM. Additionally, treatment of the
MCF-7 MDR cells with verapamil (VPL), a known P-gp efflux inhibitor, had no effect on the cellular accumulation of radiolabeled
P3. Our results provide direct evidence that the N-myristoylated pseudosubstrate peptide is taken up equivalently by drug-sensitive
and MDR cancer cells and therefore has potential value as an MDR reversal agent that operates by a novel mechanism.
Received: 27 August 1996 / Accepted: 14 January 1997 相似文献
4.
Acquired resistance to O 6-benzylguanine plus chloroethylnitrosoureas in human breast cancer 总被引:3,自引:0,他引:3
Purpose: O
6-benzylguanine (BG) is a pseudosubstrate inactivator of the DNA repair protein O
6- alkylguanine-DNA alkyltransferase (AGT) that has entered clinical trials as a potentiatier of the antitumor effect of 1,3-bis(2-chloroethyl)-1-nitrosourea
(BCNU). This study was designed to evaluate potential mechanisms of BG + BCNU resistance in breast cancer cells. Methods: We treated MCF-7 breast cancer cells three times with cytotoxic concentrations of BG + BCNU to isolate a population of MCF-7
cells possessing BG + BCNU resistance (BBR). We measured drug resistance, AGT activity, cross-resistance to other agents and
sensitivity of AGT to BG inactivation. Results: When compared with the parent line, MCF-7BBR cells were no longer sensitized to BCNU by BG, resulting in three-fold resistance
to BG + BCNU and fourfold resistance to BG + 1-(2-chloroethyl)-1-nitrosourea (CNU). In contrast, MCF-7 and MCF-7BBR cells
had similar sensitivity to BCNU, CNU, temozolomide (each in the absence of BG), cisplatin, and UV light. Acquired resistance
to BG + chloroethylnitrosoureas (CENU) in MCF-7BBR cells was not accompanied by an increase in AGT or altered kinetics of
BG inactivation of AGT. While glutathione-S transferase activity was increased modestly, its contribution to resistance in
this setting remains unclear. Conclusions: This is the first report of acquired BG + CENU resistance in human tumor cells and the results indicate that selective pressure
with BG + CENUs may result in nonresponsiveness to BG by one or more complex mechanisms. These results predict the development
of acquired resistance to BG + BCNU in clinical trials.
Received: 18 September 1998 / Accepted: 12 January 1999 相似文献
5.
Hiromitsu Jinno M. Ueda Soji Ozawa Kiyoshi Kikuchi Tadashi Ikeda Koji Enomoto Masaki Kitajima 《Cancer chemotherapy and pharmacology》1996,38(4):303-308
Mammalian pancreatic ribonuclease (RNase) was conjugated chemically via a disulfide bond to human or murine epidermal growth
factor (EGF). The conjugation between EGF and RNase was ascertained by SDS-PAGE using reduced and nonreduced conjugates. The
EGF–RNase conjugate retained potent RNase activity and competed with 125I-EGF for binding to EGFR to the same extent as unconjugated EGF. Both the human and murine EGF–RNase conjugates showed dose-dependent
cytotoxicity against EGFR- overexpressing A431 human squamous carcinoma cells with IC50 values of 3×10-7 M and 6×10-7 M, respectively, whereas free RNase had an IC50 of 10-4 M. Against the EGFR-deficient small-cell lung cancer cell line H69, the EGF–RNase conjugate had no cytotoxic effect. The Human
EGF–RNase conjugate showed dose-dependent cytotoxicity against other squamous carcinoma cell lines (TE-5, TE-1) and breast
cancer cell lines (BT-20, SK-BR-3, MCF-7) and the cytotoxicity of the conjugate correlated positively with the level of expression
of EGFR by each cell line. An unconjugated mixture of EGF and RNase had no greater effect than RNase alone on any cell line.
Excess free EGF blocked EGF–RNase conjugate cytotoxicity against A431 cells. These results suggest that the EGF–RNase conjugate
may be a more effective anticancer agent with less immunogenicity than coventional chimeric toxins.
Received: 24 March 1995/Accepted: 7 December 1995 相似文献
6.
Defects in methylthioadenosine phosphorylase are associated with but not responsible for methionine-dependent tumor cell growth 总被引:6,自引:0,他引:6
A large proportion of human tumor-derived cell lines and primary tumor cells show methionine-dependent growth. This phenomenon refers to the ability of cells to grow in media containing methionine and the inability of cells to grow in media supplemented with methionine's precursor, homocysteine (Hcy). Methionine can be formed by two different pathways, the recycling pathway and the salvage pathway. To discover the basis for methionine-dependent growth, we have analyzed 12 tumor cell lines and 2 non-tumor-derived cell lines for defects in two key genes in different methionine synthetic pathways. We found little evidence that defects in methionine synthase expression or mutations in the MS gene are correlated with methionine-dependent growth. However, we did find a correlation between methionine-dependent growth and defects in expression of methylthioadenosine phosphorylase (MTAP), a key enzyme in the salvage pathway. Three of the four cell lines lacking detectable MTAP protein were unable to grow in Hcy-containing media, whereas all six of the MTAP-positive cell lines tested showed strong growth. However, when we introduced MTAP cDNA into MTAP-deficient MCF-7 cells, the resulting cell line was still defective in growth on Hcy, although it could now grow on the salvage pathway precursor methylthioadenosine. These findings indicate that salvage pathway defects are not causally related to methionine-dependent growth. 相似文献
7.
Moore C Hernández-Santiago BI Hurwitz SJ Tan C Wang C Schinazi RF 《Journal of neuro-oncology》2005,74(3):275-280
Summary Boron–neutron capture therapy (BNCT) is based on the preferential targeting of tumor cells with 10B and subsequent irradiation with epithermal neutrons to produce a highly localized field of lethal α particles, while sparing neighboring non-targeted cells. BNCT treatment of 9L brain tumors in a rat model using β-d-5-o-carboranyl-2′-deoxyuridine (d-CDU) resulted in greater efficacy than predicted based on the assumption of a uniform tumor distribution of 10B. Thus, the geometric heterogeneity of dividing cells in brain tumors warranted studies on the cell cycle dependency of d-CDU accumulation, metabolism and entrapment in a relevant brain tumor cell system. U-271 human glioma cells were synchronized
in G1 or S-phases of the cell cycle. The cellular accumulation and phosphorylation of d-CDU was measured in the G1 and S-phase cells using high-performance liquid chromatography (HPLC). Cells synchronized in the S-phase accumulated significantly
higher amounts of d-CDU and produced larger amounts of negatively charged d-CDU monophosphate (d-CDU-MP) and nido-CDU metabolites than resting cells. Since brain tumors contain a larger proportion of cycling cells than neighboring tissue,
these results support the hypothesis that in addition to breakdown of the blood-brain-barrier (BBB) in tumors, the preferential
phosphorylation of d-CDU in cycling cells may further enrich the distribution of 10B in dividing cells. Therefore, dosimetry calculations that include the spatial distribution of cycling cells may be warranted
for d-CDU. 相似文献
8.
Purging of contaminating breast cancer cells from hematopoietic progenitor cell preparations using activation enhanced cell death 总被引:4,自引:0,他引:4
Activation enhanced cell death (AECD) involves stimulating cells with growth or activation signals while concurrently blocking
calcium influx. In this study, we have evaluated the effect of AECD on human breast cancer cells. MCF-7 or MDA-MB-231 cells
treated with Ca2+ influx blockers econazole or ketotifen for 24 h underwent a dose-dependent, irreversible loss of viability, and clonogenicity.
Two-hour treatment of these cells with higher concentrations of the drugs also resulted in loss of clonogenicity, but morphological
indicators of cell death were apparent only after longer incubation. Loss of clonogenicity could be enhanced almost 10-fold
by co-stimulation of the cells with the agonists EGF or bombesin. Econazole was also effective in inducing cell death in multi-drug
resistant MCF-7adr cells. Human hemopoietic progenitor cell sensitivity to econazole or ketotifen was evaluated by colony assay. Under conditions
resulting in 2.5–3 logs of breast cancer cell loss, 60–70% of hemopoietic progenitors could be recovered. We further evaluated
the effect of econazole on breast cancer cells present in mobilized hemopoietic cells obtained from patients undergoing high
dose chemotherapy with autologous stem cell support. In six of eight samples evaluated, cytokeratin-positive breast cancer
cells could be detected by immunofluorescence microscopy and colony formation. Breast cancer colonies were reduced 60–500-fold
or more after exposure to econazole while hemopoietic colonies were typically reduced only 2-fold. In all cases, addition
of EGF as an activator either had no evaluable effect or enhanced breast cancer cell loss. We conclude that Ca2+ influx blockade with concurrent EGF stimulation is a promising approach for purging breast cancer cells from hemopoietic
progenitor cell preparations. 相似文献
9.
Caryl J. Antalis Tyler Arnold Tamkeen Rasool Bonggi Lee Kimberly K. Buhman Rafat A. Siddiqui 《Breast cancer research and treatment》2010,122(3):661-670
The specific role of dietary fat in breast cancer progression is unclear, although a low-fat diet was associated with decreased
recurrence of estrogen receptor alpha negative (ER−) breast cancer. ER− basal-like MDA-MB-231 and MDA-MB-436 breast cancer cell lines contained a greater number of cytoplasmic lipid droplets compared
to luminal ER+ MCF-7 cells. Therefore, we studied lipid storage functions in these cells. Both triacylglycerol and cholesteryl ester (CE)
concentrations were higher in the ER− cells, but the ability to synthesize CE distinguished the two types of breast cancer cells. Higher baseline, oleic acid-
and LDL-stimulated CE concentrations were found in ER− compared to ER+ cells. The differences corresponded to greater mRNA and protein levels of acyl-CoA:cholesterol acyltransferase 1 (ACAT1),
higher ACAT activity, higher caveolin-1 protein levels, greater LDL uptake, and lower de novo cholesterol synthesis in ER− cells. Human LDL stimulated proliferation of ER− MDA-MB-231 cells, but had little effect on proliferation of ER+ MCF-7 cells. The functional significance of these findings was demonstrated by the observation that the ACAT inhibitor CP-113,818
reduced proliferation of breast cancer cells, and specifically reduced LDL-induced proliferation of ER− cells. Taken together, our studies show that a greater ability to take up, store and utilize exogenous cholesterol confers
a proliferative advantage to basal-like ER− breast cancer cells. Differences in lipid uptake and storage capability may at least partially explain the differential effect
of a low-fat diet on human breast cancer recurrence. 相似文献
10.
Kate Moynihan Gertrude B. Elion Charles Pegram Craig J. Reist Daniel Wellner Darell D. Bigner Owen W. Griffith H. S. Friedman 《Cancer chemotherapy and pharmacology》1996,39(3):179-186
These studies evaluated the efficacy of sequential pretreatment with L-amino acid oxidase (LOX) and LOX antiserum in the modulation of melphalan activity against intracranial glioma in athymic
nude mice. LOX produced statistically significant (P<0.01) depletion of the large neutral amino acids isoleucine, leucine, methionine, phenylalanine, tyrosine, and valine in
murine plasma at doses of 100 and 200 μg administered intravenously. Polyclonal anti-LOX antibody was successfully produced
in mice, rabbits, and goats subsequent to immunization with LOX. Staphylococcal protein A-purified rabbit anti-LOX serum inhibited
approximately 50% of LOX activity in vitro relative to control samples. This antiserum was used in vivo to inactivate LOX
after it had depleted the large neutral amino acids, thereby preventing LOX-mediated catabolism of melphalan. Inoculation
of three mice with rabbit anti-LOX serum after the treatment with LOX (100 μg) reduced LOX activity by 100%, 89%, and 100%
at 6 h compared with reductions of 80%, 59%, and 52% over the same period in animals receiving LOX alone. In three separate
studies using groups of eight to ten mice bearing intracranial human glioma xenografts, pretreatment with LOX followed by
anti-LOX serum increased the antitumor activity of melphalan as compared with treatments with melphalan plus LOX, melphalan
plus anti-LOX serum, or melphalan alone.
Received: 4 December 1995/Accepted: 25 May 1996 相似文献
11.
Human breast cell lines exhibit functional α2-adrenoceptors 总被引:1,自引:0,他引:1
Vázquez SM Mladovan AG Pérez C Bruzzone A Baldi A Lüthy IA 《Cancer chemotherapy and pharmacology》2006,58(1):50-61
Adrenergic compounds (epinephrine and norepinephrine) are the most important hormones released during stress. Several different
receptors are associated with their action in different tissues. However, α2-adrenoceptors have not yet been described in either normal or tumour human breast tissue. The aim of this work was to describe
and characterize these receptors in several tumour and non-tumour human cell lines. The expression of α2-adrenoceptors was analyzed at the RNA (RT-PCR) and protein ([3H]-rauwolscine binding and immunocytochemistry) levels in different human breast cell lines, and the biological activity assessed
by [3H]-thymidine incorporation. The cancer IBH-6, IBH-7 and MCF-7 and the non-tumour HBL-100 cells line, expressed both α2B- and α2C-adrenoceptor-subtypes. A single subtype was expressed in malignant HS-578T (α2A) and MDA-MB-231 and non-tumour MCF-10A cells (α2B). All cell lines exhibited significant binding for the specific antagonist [3H]-rauwolscine. The α-, α2-, and the α1-compounds with known affinity for α2-adrenoceptors, including epinephrine, norepinephrine, yohimbine, clonidine, rauwolscine and prazosin, competed significantly
with binding in MCF-7 cells. In addition, IBH-6, IBH-7 and MCF-7 cells showed significant staining with specific antibodies
against α2B- and α2C-adrenoceptor-subtypes, when tested by immunocytochemistry. In all cell lines, the specific agonist clonidine or oxymetazoline
stimulated [3H]-thymidine incorporation. EC50 values were in the range of 20–50 fM for IBH-6, IBH-7, and HS-578T; 0.14 pM for MCF-7; 2–82 pM for HBL-100 and MCF-10A cells,
and a biphasic behaviour with a maximum value at 38.0 pM, was observed for MDA-MB-231 cells. The specific α2-adrenergic antagonist rauwolscine always reversed this stimulation at 0.1 nM. In conclusion, this study describes for the
first time, the presence of α2-adrenoceptors in human epithelial breast cell lines. Moreover, activation of these receptors was associated with an enhancement
of cell proliferation. 相似文献
12.
Corte MD Tamargo F Alvarez A Rodríguez JC Vázquez J Sánchez R Lamelas ML González LO Allende MT García-Muñiz JL Fueyo A Vizoso F 《Breast cancer research and treatment》2006,96(1):63-72
Summary
Background The Trefoil Factor 1 (TFF1/pS2), a peptide consisting of 60 amino acids, is the most abundant estrogen-induced messenger RNA
present in MCF-7 breast cancer cells. The objective of this work was to evaluate the cytosolic TFF1 content in breast carcinomas,
its possible relationship with different clinical–pathological parameters, and its potential prognostic significance and predictive
value.
Methods Cytosolic TFF1 levels were examined by immunoradiometric assay in 1031 patients with invasive breast cancer. The median follow-up
period was of 50 months.
Results There was a wide variability of cytosolic TFF1 levels in tumors (0.9–743.2 ng/mg protein). Statistical analysis showed that
TFF1 levels were significantly higher in premenopausal patients (p=0.001), as well as in tumors showing any of the following characteristics: good differentiation (p=0.0001), ER and PgR positivity (p=0.0001 and p=0.001, respectively), diploidy (p=0.045) and a high S-phase fraction (p=0.001). In addition, the presence of high intratumoral TFF1 levels (cut-off: 2 ng/mg protein) was independently associated
with a shorter overall survival in the group of patients as a whole (p=0.001) as well as in the subgroup with node-negative breast cancer (p=0.0004). Likewise, high intratumoral TFF1 levels were associated with a more prolonged overall survival in patients who received
adjuvant tamoxifen (p=0.004).
Conclusions In breast cancer patients, intratumoral TFF1 levels are associated with a better clinical outcome, especially in those with
node-negative tumors. In addition, TFF1 levels have a low but significant predictive value in regards to response to adjuvant
therapy with tamoxifen. 相似文献
13.
David M. Vigushin Grace K. Poon Alan Boddy Jacqueline English Gavin W. Halbert Christos Pagonis Michael Jarman R. Charles Coombes 《Cancer chemotherapy and pharmacology》1998,42(2):111-117
Purpose: d
-Limonene is a natural monoterpene with pronounced chemotherapeutic activity and minimal toxicity in preclinical studies. A
phase I clinical trial to assess toxicity, the maximum tolerated dose (MTD) and pharmacokinetics in patients with advanced
cancer was followed by a limited phase II evaluation in breast cancer. Methods: A group of 32 patients with refractory solid tumors completed 99 courses of d-limonene 0.5 to 12 g/m2 per day administered orally in 21-day cycles. Pharmacokinetics were analyzed by liquid chromatography-mass spectrometry.
Ten additional breast cancer patients received 15 cycles of d-limonene at 8 g/m2 per day. Intratumoral monoterpene levels were measured in two patients. Results: The MTD was 8 g/m2 per day; nausea, vomiting and diarrhea were dose limiting. One partial response in a breast cancer patient on 8 g/m2 per day was maintained for 11 months; three patients with colorectal carcinoma had prolonged stable disease. There were no
responses in the phase II study. Peak plasma concentration (Cmax) for d-limonene ranged from 10.8 ± 6.7 to 20.5 ± 11.2 μM. Predominant circulating metabolites were perillic acid (Cmax 20.7 ± 13.2 to 71 ± 29.3 μM ), dihydroperillic acid (Cmax 16.6 ± 7.9 to 28.1 ± 3.1 μM ), limonene-1,2-diol (Cmax 10.1 ± 8 to 20.7 ± 8.6 μM ), uroterpenol (Cmax 14.3 ± 1.5 to 45.1 ± 1.8 μM ), and an isomer of perillic acid. Both isomers of perillic acid, and cis and trans isomers of dihydroperillic acid were in urine hydrolysates. Intratumoral levels of d-limonene and uroterpenol exceeded the corresponding plasma levels. Other metabolites were trace constituents in tissue. Conclusions:
d-Limonene is well tolerated in cancer patients at doses which may have clinical activity. The favorable toxicity profile supports
further clinical evaluation.
Received: 25 June 1997 / Accepted: 6 November 1997 相似文献
14.
Jörg Stüben Rüdiger Port Barbara Bertram Ursula Bollow William E. Hull Marianne Schaper Jörg Pohl M. Wiessler 《Cancer chemotherapy and pharmacology》1996,38(4):355-365
β-D-Glucosylisophosphoramide mustard (β-DGlc-IPM) is a new, potential chemotherapeutic agent currently under investigation. Its pharmacokinetics in plasma and elimination
of the parent drug and its metabolites via urine, bile, and exhaled air were studied in female Sprague-Dawley rats after bolus
injection of 315 mg/kg. Typically, the drug’s disposition from plasma follows a linear two-compartment model with half-lives
(t
1/2) of 1.8 (t
1/2α) and 32 min (t
1/2β). The rate of clearance is 0.0046 (range 0.0030–0.0071) l min-1 kg-1, and the steady-state volume of distribution (V
ss) is 0.18 (0.08–0.042) l/kg (mean±interindividual standard deviation). In human plasma, 28.1±2.6% (mean±SD) of the drug (concentration
range 0.5–5 mg/ml) is bound to plasma proteins (predominantly to albumin). Biliary excretion of the parent drug accounts for
2.9±1.7% of the dose; its elimination in the form of 14CO2 via exhaled air is less than 1%. Within 24 h, 63.5±4.9% of the 14C-labeled drug is excreted unchanged in the urine, whereas 17.5±5.1% is excreted in the urine as metabolites. In addition,
β-D-Glc-[14C]-IPM was given as a bolus injection to female Sprague-Dawley rats at dose levels of 315 and 56.2 mg/kg. The distribution
of radioactivity into tissue was examined qualitatively by whole-body autoradiography (WBA). Parallel experiments were carried
out using the high dose of the L-derivative. After dosing with the D-compound, the highest levels of radioactivity were found in the liver, kidneys, thymus, thyroid gland, and central nervous
system, including the brain. A similar distribution pattern was observed for the L-compound, except in the brain, which contained negligible levels of radioactivity. The distribution of the D-compound (high dose) was also investigated in male Copenhagen rats bearing a Dunning prostate tumor. The results were similar
to those obtained in healthy Sprague-Dawley rats. Additionally, radioactivity was found in the tumor at 1 h after dosing with
the drug and remained there even after 24 h. The effects of β-D-Glc-IPM on the incorporation of [methyl-3H]-thymidine into the DNA of the liver, kidneys, thymus, spleen, esophagus, and bone marrow of the rat were examined following
tissue excision and liquid scintillation counting at 2, 8, and 24 h after administration of the drug. β-D-Glc-IPM showed no effect on the incorporation of [methyl-3H]-thymidine in the liver and an insignificant reduction in kidney DNA (maximal reduction: −27.3%). However, after 8 h there
was a marked reduction in the incorporation rate in the thymus (−83.7%), spleen (−74.6%), and esophagus (−87.2%), with a tendency
toward recovery within 24 h. In bone marrow cells a reduction of −75.5% (8 h) and −73.3% (24 h) was observed.
Received: 15 March 1995/Accepted: 6 October 1995 相似文献
15.
Purpose: 1,3,6,8-Substituted alkyl polychlorinated dibenzofurans (PCDFs), typified by 6-methyl-1,3,8-triCDF (MCDF), inhibit 17β-estradiol
(E2)-induced responses in the rodent uterus and human breast cancer cells. The major purpose of the experiments reported here
was to determine the structure-dependent antiestrogenic activities of several alternate-substituted (1,3,6,8- and 2,4,6,8-)
PCDFs. Methods: The antiestrogenic activities were determined in MCF-7 human breast cancer cells using two assays, that is E2-induced cell
proliferation and induction of chloramphenicol acetyl transferase (CAT) activity in cells transiently transfected with the
E2-responsive Vit-CAT plasmid. Results: MCDF (10−5 M ), 6-isopropyl-1,3,8-triCDF, 6-ethyl-1,3,8-triCDF, 3-isopropyl-6-methyl-1,8-diCDF, and 6-methyl-2,4,8-triCDF, inhibited both
E2-induced cell proliferation and CAT activity in MCF-7 cells. All of the remaining ten congeners inhibited either E2-induced
cell proliferation or CAT activity, but not both responses. Conclusions: The antiestrogenic activity of the alternate-substituted PCDFs involves interactions between the aryl hydrocarbon and estrogen
receptor signaling pathways. Although these compounds exhibited antiestrogenic activity in MCF-7 cells, the effects of individual
congeners were response-specific, and there were no apparent structure-activity relationships.
Received: 26 July 1996 / Accepted: 16 November 1996 相似文献
16.
Temporal evaluation of methionine synthase and related metabolites in the MAC15A mouse adenocarcinoma animal model 总被引:2,自引:0,他引:2
Blackburn A Bibby MC Lucock MD Nicolaou A 《International journal of cancer. Journal international du cancer》2004,112(4):577-584
Methionine dependence is unique to cancer cells and defined as the inability to grow in a methionine-deprived environment even if supplemented with the metabolic precursor homocysteine. Cobalamin-dependent methionine synthase (MS) catalyses the formation of methionine and tetrahydrofolate from homocysteine and methyltetrahydrofolate, thus linking the methionine and folate pathways. The apparent altered methionine metabolism in methionine-dependent cancer cells suggests a role for MS, although results to date are conflicting. We have analysed key metabolites of the MS-associated transmethylation, transsulphuration and folate pathways of the methionine-dependent MAC15A tumour model as a function of tumour progression over a 10-day period. MS activity increased 2-fold from day 1 to day 10. Cysteine, homocysteine, S-adenosylmethionine and S-adenosylhomocysteine levels in tumour cytosolic fractions decreased as a function of tumour progression. Plasma cysteine levels also decreased, whilst the distribution of folates in erythrocytes was altered, with a maximum increase in methyltetrahydrofolate observed by day 5. The increasing MS activity and decreasing cysteine levels suggest an increasing methionine requirement by the tumour, whilst the induction of enzyme activity indicates that MS is not defective in the methionine-dependent MAC15A tumour. The decrease in tumour S-adenosylmethionine and S-adenosylhomocysteine levels suggests that methionine is required for some function other than cellular methylation, e.g., incorporation into protein. Overall, the results support a theory of methionine conservation in response to tumour growth, where the methionine-dependent MAC15A tumour has a higher than normal methionine requirement. 相似文献
17.
Muindi JR Peng Y Wilson JW Johnson CS Branch RA Trump DL 《Cancer chemotherapy and pharmacology》2007,59(1):97-104
Purpose: To determine, in peripheral blood monocytes (PBM), whether the enzymatic activities of fructose 1,6-bisphosphatase (FBPase), cytidine deaminase (CDDase) and 24-hydroxylase (CYP24), enzymes regulated by calcitriol are useful pharmacodynamic (PD) measures of calcitriol effects in cancer patients. Methods: Cancer patients enrolled in a phase I clinical trial of calcitriol and carboplatin were studied. Baseline and calcitriol-induced changes in FBPase, CDDase and CYP24 activities were measured in PBM collected before, 6, 24, and 48 h after administration of calcitriol, prior to carboplatin, in doses ranging from 4 to 11 μg daily for 3 consecutive days (QD×3). Normal FBPase, CYP24 and CDDase activities were measured in PBM from untreated healthy volunteers. Results: Baseline activities in PBM from cancer patients and healthy volunteers were (median and range): 1.0 (0.0–43.5) and 4.4 (3.1– 8.2) nmol/min/mg protein for FBPase (P = 0.002); 2.5 (0.9–9.3) and 0.8 (0.4–2.0) fmol/h/106 cells for CYP24 (P = 0.016), and 5.6 (2.5–22.3) and 6.6 (1.1–47.4) nmol/min/mg protein for CDDase (P > 0.05), respectively. All calcitriol doses achieved peak serum calcitriol levels > ×3 the physiological levels, increased cancer patient PBM FBPase activity to normal levels and decreased CDDase activity to undetectable levels within 48 h, with no significant change in CYP24 activity. These enzyme activity changes were not associated with hypercalcemia. Conclusions: Calcitriol treatment-induced increase in FBPase and decrease in CDDase activities in cancer patient PBM are potential early and sensitive non-hypercalcemia PD measures of calcitriol effects. 相似文献
18.
Michael J. Willhauck Dennis J. O`Kane Nathalie Wunderlich Burkhard Göke Christine Spitzweg 《Breast cancer research and treatment》2011,125(2):377-386
The sodium iodide symporter (NIS) mediates the active iodide uptake in the thyroid gland as well as lactating breast tissue.
Recently, we reported significant stimulation of all-trans retinoic acid (atRA)-induced NIS expression in the estrogen-receptor positive human breast cancer cell line MCF-7 by dexamethasone
(Dex) in vitro and in vivo, which might offer the potential to image and treat breast cancer with radioiodine. In this study,
based on its known interaction with the pregnane-X-receptor (PXR) forming a heterodimer with the retinoid-X-receptor (RXR),
we examined the effect of carbamazepine (CBZ), a potent activator of PXR, on atRA-induced NIS expression and therapeutic efficacy
of 131I in MCF-7 cells. For this purpose, functional NIS expression in MCF-7 cells was examined by iodide uptake assay, quantitative
real-time PCR as well as Western blot analysis, followed by investigation of 131I cytotoxicity in vitro after incubation with CBZ (4, 25, 100 μM) in the presence of atRA (1 μM) with or without Dex (100
nM). Incubation with CBZ stimulated atRA-induced iodide accumulation up to twofold in a concentration-dependent manner, while
atRA/Dex-stimulated iodide uptake was further stimulated up to 1.5-fold by additional CBZ treatment based on significantly
increased NIS mRNA and protein levels. This stimulatory effect of CBZ was shown to be dependent on the PI3K-Akt pathway without
involvement of mTOR. In contrast, treatment with CBZ alone had no effect on functional NIS expression. Moreover, selective
cytotoxicity of 131I was significantly increased from approximately 20% in MCF-7 cells treated with atRA alone to 50% after treatment with CBZ
in the presence of atRA, which was further enhanced to 90% after combined treatment with atRA/Dex/CBZ. In conclusion, CBZ
represents another potent stimulator of atRA-induced functional NIS expression resulting in an enhanced selective killing
effect of 131I in MCF-7 breast cancer cells. 相似文献
19.
Henk-Jan Guchelaar Istvan Vermes Richard P. Koopmans Chris P. M. Reutelingsperger Clemens Haanen 《Cancer chemotherapy and pharmacology》1998,42(1):77-83
Purpose: The purpose of this study was to characterize the concentration-dependent induction of apoptosis by anticancer drugs in vitro.
Methods: The apoptosis- and necrosis-inducing potential of the anticancer drugs cladribine (CDA), cytarabine (ARA-C), cisplatin (CDDP),
and 5-fluorouracil (5FU) were studied in vitro in the human leukemia cell lines HSB2 and Jurkat using a flow-cytometry assay
that permits the simultaneous quantification of vital, apoptotic, and necrotic cells by double-staining with fluorescein isothiocyanate
(FITC)-labeled Annexin-V and propidium iodide. The results were fit to different multicompartmental models and the sensitivity
of the cell lines to apoptosis and necrosis was estimated. Results: A time- and dose-dependent decrease in vital cells as well as an increase in apoptotic and necrotic cells was observed in
HSB2 cells upon continuous incubation with 10−5–10−7
M CDA, 10−5–10−8
M ARA-C, 5 × 10−5–5 × 10−6
M CDDP, and 10−4–10−5
M 5FU, whereas no effect was observed relative to controls upon incubation with 10−8–10−9
M CDA, 10−9
M ARA-C, 10−7–10−8
M CDDP, or 10−6–10−9
M 5FU. In Jurkat cells, apoptosis- and necrosis-inducing effects were observed at 10−4–5 × 10−6
M CDA, 10−5–10−7
M ARA-C, 5 × 10−5–5 × 10−6
M CDDP, and 10−4–10−5
M 5FU. In all experiments, apoptotic cells reached a peak after 6–48 h of drug exposure. These data were best fit by a model
in which vital cells became irreversibly apoptotic by a direct pathway and necrotic by an irreversible indirect pathway following
the apoptotic state (mean R=0.9876; range 0.9510–0.9993; mean modified Akaike's information criterion 3.88; range 1.86–5.82) and the rate constants of
either pathway (Kva and Kan, respectively) were assessed. The sensitivity of both cell lines to apoptosis and necrosis (expressed
as EC50 and Emax values) induced by the anticancer drugs could be calculated from the sigmoidal concentration-effect curves. Furthermore,
it was shown that drug treatment (10−6
M CDA or 10−6
M ARA-C) potentiated the apoptosis-inducing effects of irradiation (6 Gy) but not its necrosis-inducing potential. Conclusion: This study demonstrates that CDA, ARA-C, CDDP, and 5FU possess concentration-dependent apoptosis-inducing potential in the
cell lines studied. The cytotoxic mechanism and cell-killing potential of these drugs is different, which is reflected by
different EC50 and Emax values. Furthermore, a method for pharmacodynamic modeling is introduced that permits a quantitative approach for the assessment
of the sensitivity of tumor cells to anticancer drugs and combined treatments.
Received: 13 July 1997 / Accepted: 5 November 1997 相似文献
20.
Summary We previously identified a CD2-initiated signaling pathway which inhibits activation-induced cell death in mitogen-stimulated
human γδ-T cells permitting the large-scale expansion of these cells. Here we report the innate anti-tumor activity of expanded human
γδ-T cells against human breast cancer cells. Apoptosis-resistant human γδ-T cells which were expanded in vitro from cultured human peripheral blood mononuclear cells displayed lytic activity against breast cancer cell lines MDA-MB-231,
MCF-7 and T-47D, but failed to kill normal human skin fibroblasts and normal human liver cells. Monoclonal antibodies (mAb)
directed against the γδ-T cell receptor (TCR) or mAb directed against either the Vγ9 or the Vδ2 TCR chains were able to block γδ-T cell-mediated lysis of MDA-MB-231 cells. In addition, mAb against intercellular adhesion molecules-1 (ICAM-1/CD54) or CD18
(β subunit of ICAM-1 counter–receptor) also blocked γδ-T cell-mediated killing of MDA-MB-231 cells. Ex vivo expanded human γδ-T cells are thus able to innately recognize and kill human breast cancer cells in a γδ-TCR-dependent manner; ICAM-1 and CD18 also appear to be involved in the interactions between sensitive breast cancer cells
and cytolytic γδ-T cells. As apoptosis-resistant human γδ-T cells can now readily be expanded to large numbers (clinical scale), these findings must be considered in the context of
developing adoptive immunotherapy strategies to exploit γδ-T cell innate immune responses for the primary or adjuvant treatment of breast cancer. 相似文献