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  • chemotherapy  (36)
  • 1
    Keywords: Rb ; PKB/AKT ; lipid ; mechanism of action ; erufosine ; synergistic combinations ; pAkt ; BCR-ABL ; CML ; caspases ; KINASE INHIBITOR ; LEVEL ; INCREASE ; SUBSTRATE ; AGENT ; signaling ; CASPASE ; INHIBITORS ; protein expression ; MAMMALIAN-CELLS ; PROTEIN-KINASE-C ; leukemia ; FUSION ; LINE ; MEMBRANE ; SIGNAL-TRANSDUCTION ; COMPONENT ; ALKYLPHOSPHOCHOLINES ; ANTILEUKEMIC EFFICACY ; CELL-LINE ; chemotherapy ; cell lines ; p27 ; ENTRY ; HEALTH ; ASSAY ; PROGRESSION ; SIGNAL ; treatment ; TYROSINE KINASE INHIBITOR ; CYCLE ; CELL-LINES ; CELL-CYCLE ; cell cycle ; PROTEIN-KINASE ; signal transduction ; INDUCTION ; REDUCTION ; TYROSINE KINASE ; COMBINATION ; KINASE ; PATHWAY ; THERAPY ; PATHWAYS ; CELL ; INHIBITOR ; APOPTOSIS ; EXPRESSION ; CELLS ; DISEASE ; NEW-YORK ; LINES ; cell line ; DRUG ; PROTEINS ; PROTEIN ; TRANSDUCTION ; cell signaling ; MECHANISM ; PATIENT
    Abstract: The ether lipid analog erufosine (erucylphospho-N,N,N,- trimethylpropylammonium, ErPC3) has high activity against leukemic cells without affecting the normal hematopoiesis. It belongs to the group of alkylphosphocholines (APC) that are inhibitors of protein kinase C and phospholipase C. However, the mechanism of action of erufosine remains rather unclear. We focused on combination effects with the tyrosine kinase inhibitor imatinib mesylate (gleevec, former STI-571 or CGP-57148) against two chronic myeloid leukemia (CML)-derived cell lines (K-562 and BV-173). The influence of erufosine on proteins involved in the phosphatidylinositol-3-phosphate pathway and on expression of the retinoblastoma protein Rb was studied, the latter being a key component for cell cycle entry and progression in mammalian cells. The consecutive treatment of K-562 and BV-173 cells with erufosine (2.5, 5, 15, 30 mu M) and imatinib mesylate (0.05, 0.1 mu M) led to synergism as measured by the MTT-dye reduction assay and this is reason to hypothesize that such combinations could be beneficial for relapsed patients with drug-resistant disease. Whole cell lysates from K-562 and BV-173 were investigated for the expression of Rb, PKB/Akt, pAkt, and p27 by Western blot. Erufosine caused decreases of pAkt and CML fusion protein p210 (BCR-ABL) protein expression, but induced the Rb protein expression in K-562 cells. A parallel increase in p27 level was observed after 24 and 48 h treatment. These alterations in signal transduction could be an explanation for the drug interaction found. Furthermore, Rb is a substrate of caspases and is cleaved during apoptosis as already evidenced for BV-173 cells. Our experimental findings suggest that erufosine acts through induction of changes in protein signaling and especially through Rb induction. This unique mode of action makes it an attractive partner for combination therapies, for example, in combination with imatinib mesylate for treatment of CML
    Type of Publication: Book chapter
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  • 2
    Keywords: CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; proliferation ; TUMOR-CELLS ; CELL ; Germany ; human ; MODEL ; PROTEIN ; PROTEINS ; REDUCTION ; MR ; BREAST ; breast cancer ; BREAST-CANCER ; antibodies ; antibody ; GLYCOPROTEIN ; TARGET ; ASSAY ; METASTASIS ; PROSTATE-CANCER ; chemotherapy ; oligonucleotides ; CANCER-CELLS ; MIGRATION ; PROGNOSTIC VALUE ; GREECE ; GREEN FLUORESCENT PROTEIN ; ANTISENSE OLIGONUCLEOTIDES ; HUMAN BREAST ; GFP-MDA-MB-231,migration,metastasis,antisense oligonucleotides,osteopontin,bone sialoprotein ; HUMAN BREAST-CANCER ; SPARC
    Abstract: MDA-MB-231 human breast cancer cells transfected with GFP were used as model to determine the reduction in proliferation, colony formation, and migration in response to agents with anti-metastatic properties. These agents consisted of antisense oligonucleotides (ASOs) directed against osteopontin (OPN), bone sialoprotein II (BSP II), and osteonectin (ON), as well as an antibody directed against BSP II. A bisphosphonate derivative (ibandronate) and an alkylphosphocholine (erucylphospho-NNN-trimethylpropanolamine; ErPC3) were used as positive controls. The ASOs directed against OPN, BSP II and ON suppressed the expression of their respective target proteins by 81%, 74% and 69%, respectively. They were barely but significantly active in inhibiting the proliferation, but intermediately to highly active in inhibiting the colony formation and migration of GFP-MDA-MB-231 breast cancer cells. The antibody against human BSP II was significantly more active than all ASOs used and was equally active or even surpassed the activity of ibandronate and ErPC3 in all three assays. The results obtained suggest a specific anti-metastatic activity of this antibody as well as of the ASOs found effective in decreasing OPN and BSP II expression
    Type of Publication: Journal article published
    PubMed ID: 15067347
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  • 3
    Keywords: CANCER ; CELLS ; tumor ; carcinoma ; CELL ; evaluation ; Germany ; incidence ; liver ; SAMPLE ; SAMPLES ; PATIENT ; MESSENGER-RNA ; primary ; CONTRAST ; LYMPH-NODES ; MR ; SEQUENCE ; BONE-MARROW ; STAGE ; PATTERNS ; ASSAY ; MUTATION ; COLORECTAL-CANCER ; chemotherapy ; MARKERS ; WILD-TYPE ; COLON-CANCER ; MUTATIONS ; ONCOGENE ; EPITHELIAL-CELLS ; CANCER-PATIENTS ; CARCINOMAS ; COLORECTAL CARCINOMAS ; MICROMETASTASES ; POLYMERASE-CHAIN-REACTION ; PROGNOSTIC-SIGNIFICANCE ; RT-PCR ; GREECE ; CANCER PATIENTS ; PERIPHERAL-BLOOD ; NODES ; COLORECTAL-CARCINOMA ; disseminated tumor cells,circulating epithelial cells,K-ras,cytokeratin 20,guanylylcyclase C ; GUANYLYL CYCLASE-C
    Abstract: The aim of this prospective study was to relate the incidences of cytokeratin 20 (CK20) and guanylylcyclase C (GCC) in lymph node, liver, and bone marrow specimens of 245 colorectal cancer (CRC) patients with the K-ras oncogene status of the corresponding primary tumor. Qualitative RT-PCR detection of CK20 and GCC mRNA was used as marker of circulating epithelial cells (CEC). Samples were considered positive for CEC only when both markers were detected concomitantly. For the detection of K-ras mutations, a PCR-RFLP assay was used. In the group with K-ras mutated primary carcinomas (n=92), CEC were detected in 62% of lymph node-, 43% of liver-, and 2% of bone marrow samples. No statistical significance was found when comparing these results with those from patients with K-ras wild-type carcinoma (59%, 46%, and 0%, respectively). In contrast to this combined evaluation, separate analysis of K-ras codons 12 (n=75, 82%) and 13 (n=17, 18%) revealed significantly differing CEC incidences. Lymph node specimens from corresponding K-ras codon 13 mutated carcinomas showed a significantly higher CEC incidence (82%) than the groups with codon 12 mutation (57%, p〈0.05) or K-ras wild-type sequence (59%, p〈0.05). Unlike these findings in lymph nodes, liver biopsies from corresponding carcinomas with K-ras codon 12 mutation or wild-type sequence were significantly more often positive for CEC (31% and 29%) than specimens from K-ras codon 13 mutated primary CRC (12%, p〈0.04, respectively). In conclusion, colorectal carcinomas with K-ras codon 12 mutation showed the same pattern of tumor cell dissemination as their K-ras wild-type counterparts. Since K-ras codon 12 mutations prevailed 4-fold over codon 13 mutations, combined analysis of the two codons showed the same result. However, sub-analysis of patients with K-ras codon 13 mutation revealed that the respective CEC incidence was significantly increased in lymph nodes, but decreased in liver biopsies
    Type of Publication: Journal article published
    PubMed ID: 15138598
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  • 4
    Keywords: CANCER ; GROWTH ; SURVIVAL ; tumor ; COMBINATION ; Germany ; human ; LUNG ; THERAPY ; DIAGNOSIS ; DISEASE ; DRUG ; TUMORS ; LINES ; PATIENT ; colon ; CELL-LINES ; treatment ; TRIAL ; EXPERIENCE ; NUMBER ; metastases ; CELL-LINE ; chemotherapy ; leukemia ; LINE ; MELANOMA ; DERIVATIVES ; COLON-CANCER ; CANCER-PATIENTS ; SAFETY ; CANCER PATIENTS ; RANDOMIZED TRIAL ; cell lines ; DACARBAZINE ; RANDOMIZED-TRIAL ; FOTEMUSTINE ; INTERLEUKIN-2 ; CYTOTOXICITY ; STANDARD ; ONCOLOGY ; colon cancer ; TUMOR-GROWTH ; HUMAN CANCER ; IV ; CHINESE ; uveal melanoma ; MALARIA ; antimalarial ; artemisinin ; artesunate ; DIHYDROARTEMISININ ; HOLOTRANSFERRIN ; QINGHAOSU ; TOLERABILITY ; uvea
    Abstract: Artesunate (ART) is a derivative of artemisinin, the active principle of the Chinese herb Artemisia annua L. Artesunate is approved for the treatment of multidrug-resistant malaria and has an excellent safety profile. It has been shown that Artesunate, apart from its anti-malarial activity, has cytotoxic effects on a number of human cancer cell lines, including leukemia, colon cancer and melanoma. We report on the first long-term treatment of two cancer patients with ART in combination with standard chemotherapy. These patients with metastatic uveal melanoma were treated on a compassionate-use basis, after standard chemotherapy alone was ineffective in stopping tumor growth. The therapy-regimen was well tolerated with no additional side effects other than those caused by standard chemotherapy alone. One patient experienced a temporary response after the addition of ART to Fotemustine while the disease was progressing under therapy with Fotemustine alone. The second patient first experienced a stabilization of the disease after the addition of ART to Dacarbazine, followed by objective regressions of splenic and lung metastases. This patient is still alive 47 months after first diagnosis of stage IV uveal melanoma, a situation with a median survival of 2-5 months. Despite the small number of treated patients, ART might be a promising adjuvant drug for the treatment of melanoma and possibly other tumors in combination with standard chemotherapy. Its good tolerability and lack of serious side effects will facilitate prospective randomized trials in the near future
    Type of Publication: Journal article published
    PubMed ID: 16273263
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  • 5
    Keywords: CANCER ; CELLS ; GROWTH ; IN-VITRO ; proliferation ; tumor ; TUMOR-CELLS ; AGENTS ; CELL LUNG-CANCER ; COMBINATION ; Germany ; IN-VIVO ; INHIBITION ; MODEL ; VITRO ; EXPOSURE ; liver ; PATIENT ; RAT ; RATS ; SEQUENCE ; RAT-LIVER ; ASSAY ; METASTASIS ; colorectal cancer ; COLORECTAL-CANCER ; EFFICACY ; metastases ; chemotherapy ; arteries ; CANCER-CELLS ; COLON-CANCER ; LIVER METASTASES ; BOLUS ; AGENT ; GEMCITABINE ; colon cancer ; TUMOR-GROWTH ; END ; COLON ADENOCARCINOMA ; HEPATIC METASTASES ; PHASE-II TRIAL ; STARCH MICROSPHERES ; ANIMAL-MODEL ; liver metastasis ; PEMETREXED DISODIUM ; CC531-lac-Z ; chemoembolization ; chemoluminescence ; INTRAARTERIAL CHEMOTHERAPY ; MULTITARGETED ANTIFOLATE LY231514 ; SELECTIVE CHEMOEMBOLIZATION
    Abstract: Purpose: The aim of this study was to evaluate the combination effect of pemetrexed disodium (MTA; Alimta; LY 231514) and gemcitabine ( GEM) administered by hepatic artery and portal vein chemoembolization (HACE and PVCE) in a colorectal cancer rat liver metastasis model. Materials and methods: Proliferation studies on CC531-lac-Z rat colon cancer cells were performed using the MTT assay to obtain the optimal combination schedule of the two antineoplastic agents. To generate diffuse liver metastasis, 4 x 10(6) tumor cells were implanted into the portal vein of male WAG/Rij rats. MTA ( 30 mg/kg, 60 mg/kg, and 90 mg/kg) was administered locoregionally by portal vein chemoembolization ( PVCE) and compared with repeated systemic intravenous injection. GEM ( 50 mg/kg) was also given locoregionally by hepatic artery chemoembolization ( HACE) as well as systemically. All routes of administration were examined alone as well as in combination. Efficacy of treatment in terms of liver metastases burden was determined at the end of the experiment by measuring the beta-galactosidase activity of CC531-lac-Z cells with a chemoluminescence assay. Results: Combination experiments in vitro showed a more than additive tumor cell reduction after sequential exposure to MTA preceding GEM (observed/expected ratio [O/ E] = 0.73). Experiments with the reverse sequence ( GEM. MTA) resulted only in additive combination effects ( O/ E ratio = 1.08). Simultaneous drug exposure showed less than additive combination effects (O/ E ratios 〉= 1.25). In vivo, locoregional administration by HACE with GEM was significantly more effective than systemic intravenous bolus treatment (P = 0.03). Portal vein chemoembolization with MTA performed immediately after tumor cell inoculation was ineffective. Repeated systemic treatment with MTA yielded a slight reduction in tumor cell load that was significant versus control at the medium and high doses ( 60 mg/kg, P = 0.009; 90 mg/kg, P = 0.046) but not versus intraportal chemoembolization. The combination treatment of systemic ( 60 and 90 mg/kg) or locoregional ( 60 mg/kg) MTA with HACE using GEM ( 50 mg/kg) resulted in more than 80 % tumor growth inhibition; this antineoplastic combination effect was maximally additive. Conclusion: A regimen-dependent synergistic combination effect of both drugs was found in vitro. In animals, hepatic artery chemoembolization with GEM was superior to systemic intravenous bolus treatment. Portal vein chemoembolization with MTA was ineffective. The optimal in vitro regimen of MTA ( intravenous or PVCE) preceding GEM ( HACE) resulted in a maximally additive tumor growth inhibition. The results indicate that MTA and GEM can successfully be combined and favor further evaluation in patients
    Type of Publication: Journal article published
    PubMed ID: 15657768
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  • 6
    Keywords: CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; IN-VITRO ; proliferation ; carcinoma ; Germany ; VITRO ; LUNG-CANCER ; PROTEIN ; PATIENT ; RATS ; treatment ; BREAST ; breast cancer ; BREAST-CANCER ; antibodies ; LESIONS ; METASTASIS ; NUDE-MICE ; chemotherapy ; CANCER-CELLS ; MIGRATION ; INTEGRIN ALPHA(V)BETA(3) ; SERUM ; MATRIX ; MATRIX METALLOPROTEINASES ; anti-BSP antibody ; bone metastasis ; COLONY FORMATION ; MDA-MB-231 human breast cancer cell line ; nude rat model ; OSTEOPONTIN ; bone sialoprotein
    Abstract: The extracellular bone matrix protein bone sialoprotein (BSP) is considered to play an important role in the pathogenesis of lytic skeletal lesions which are associated with severe morbidity in breast, prostate or lung cancer patients. In addition to in vitro Studies, nude rats were implanted with 105 MDA-MB-231 cells transfected with GFP into a small branch of the femoral artery. Osteolytic lesions of the respective hind leg were detected by X-ray and CT analysis as well as by inimunohistochemistry. Exposure of MDA-MB-231(GFP) cells in vitro to an antibody against BSP (0-400 mu g/ml) decreased proliferation, colony formation and migration of these cells by up to 95, 83 and 89 T/C%, respectively. In nude rats, preincubation of MDA-MB-231GFP cells prior to inoculation (25-100 mu g/ml) reduced the mean osteolytic lesion size to 22 T/C% after 90 days of observation (p 〈 0.05). Treatment of overt lytic metastasis with the anti-BSP antibody (10 mg/kg) resulted in a significantly smaller mean lesion size of 57 T/C% at the end of the observation period (p 〈 0.05) as well as in new bone formation. Immunohistochemical analysis revealed the presence of BSP in MDA-MB-231(GFP) cells and in vessel endothelium cells during processes such as migration and invasion. In conclusion, an anti-BSP antibody decreased proliferation, colony formation and migration of MDA-MB-231(GFP) cells in vitro and reduced osteolysis besides inducing bone formation in a nude rat model
    Type of Publication: Journal article published
    PubMed ID: 16465361
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  • 7
    Keywords: APOPTOSIS ; CANCER ; CELLS ; GROWTH ; INHIBITOR ; proliferation ; CELL ; COMBINATION ; INHIBITION ; PATHWAY ; PATHWAYS ; TOXICITY ; transcription ; cell line ; LINES ; MICE ; TRANSDUCTION ; PATIENT ; NF-KAPPA-B ; ACTIVATION ; TRANSCRIPTION FACTOR ; REDUCTION ; CELL-LINES ; signal transduction ; SIGNAL ; ANTITUMOR-ACTIVITY ; BONE-MARROW ; culture ; LYMPHOMA ; GLUTATHIONE ; CHROMOSOMAL-ABERRATIONS ; EFFICACY ; SIGNAL-TRANSDUCTION ; CELL-LINE ; chemotherapy ; leukemia ; LINE ; ABERRATIONS ; NF-kappa B ; CISPLATIN ; curcumin ; FACTOR-I ; cell lines ; CANCER-THERAPY ; MULTIPLE-MYELOMA ; CYTOTOXICITY ; ARREST ; multiple myeloma ; INCREASE ; LEVEL ; ASSAYS ; CANCERS ; ENGLAND ; aberration ; antineoplasic effect ; antitumor activity ; bendamustine ; chemoprotection ; clastogenic effect ; GSH level ; myeloma ; ACAD
    Abstract: Curcumin is the pigment of turmeric and has been reported as a signal transduction modulator and inhibitor of transcription factors, for example, NF-kappa B. In our article we found a concentration-dependent cytotoxic activity of curcumin in a panel of eight leukemic cell lines (SKW-3, CEM, U-937, HL-60, HL-60/Dox, K-562, LAMA-84, and AR-230). Additive to synergistic interactions was recorded for combinations with bendamustine and idarubicine in SKW-3 and LAMA-84 cells. Noteworthy, in multiple myeloma cells (RPMI-8226 and U-266) a potentiation of the efficacy of bendamustine by curcumin application was found. Moreover, curcumin increased the bendamustine cytotoxicity in cultures of cells isolated from the bone marrow of a patient with non-Hodgkin's lymphoma (NHL). The increased bendamustine efficacy could be explained by NF-kappa B inhibition, because this factor is activated in many cancers, especially leukemia and multiple myeloma. Curcumin is characterized by low toxicity and was described to have a chemoprotective activity. Therefore, the level of reduced glutathione (GSH) was measured and a concentration-dependent increase of GSH levels was recorded in AR-230 and SKW-3 cells (concentration range 5-25 mu M). Experiments with mice showed significant protection against cisplatin-induced chromosomal aberrations (clastogenic effect) and inhibition of mitoses in bone marrow cells. Curcumin alone caused reduction of the mitotic index. In combination with cisplatin, however, this parameter was increased when compared to cisplatin alone. Our data indicate that curcumin has pleiotropic effects on signal transduction by inhibiting transcription thus exerting antitumor activity. In addition, curcumin has protective and anticlastogenic activity by enhancing the scavenging of free radicals
    Type of Publication: Journal article published
    PubMed ID: 17404048
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  • 8
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; EXPOSURE ; PROTEIN ; DRUG ; cell line ; LINES ; MECHANISM ; SUFFICIENT ; MR ; CELL-LINES ; treatment ; NO ; ASSAY ; EFFICACY ; ALKYLPHOSPHOCHOLINES ; ANTILEUKEMIC EFFICACY ; CELL-LINE ; chemotherapy ; LINE ; MODULATION ; p53 ; BETA ; Jun ; sensitivity ; cell lines ; ONCOLOGY ; RE ; TUMOR-SUPPRESSOR ; LEVEL ; ASSAYS ; SUPPRESSOR ; technique ; USA ; UNIT ; mechanism of action ; Rb ; antisense ; ANTINEOPLASTIC ACTIVITY ; chronic myeloid leukemia (CML) ; cytotoxic efficacy ; erucylphospho-N,N,N-trimethylpropylammonium (erufosine)
    Abstract: The alkylphosphocholine erucylphospho-N,N,N-trimethylpropylammonium (ErPC3) is a promising new drug for treating various types of cancer. Its mechanism of action is no yet fully understood but is related to the Rb tumor suppressor protein. In the present study. we investigated the role of decreased Rb expression levels for the antileukemic efficacy of ErPC3 in BV-173 and K-562 CML-derived cell lines. We used antisense technique to knock down Rb levels in the two cell lines in addition to ErPC3 treatment. Cells with reduced Rb expression showed a diminished sensitivity to ErPC3 exposure, as determinec by MTT (BV 173 and K-562) and clonogenicity assays (K-562 only), if concentration. below the IC50 were used. The feasibility of Rb knockdown varied between BV-173 and K-562 cells, with the former being distinctly more sensitive than the latter. We conclude that sufficient Rb levels are important for the cytotoxic and anticlonogenic effects of ErPC; at levels below the IC50, but that higher concentrations of ErPC3 are less dependent or Rb status
    Type of Publication: Journal article published
    PubMed ID: 17495525
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  • 9
    Keywords: APOPTOSIS ; PATHWAYS ; DEATH ; MESSENGER-RNA ; IDENTIFICATION ; chemotherapy ; PROGRESS ; Anti-cancer ; ENDOPLASMIC-RETICULUM-STRESS ; ACTIVATING TRANSCRIPTION FACTOR-3 ; Bio-weapon ; Depurination ; RICIN ; RIP ; Riproximin ; UPR ; Volkensin ; XIMENIA-AMERICANA
    Abstract: Cytotoxic ribosome-inactivating proteins (RIPs) of type II such as ricin were investigated as anti-cancer agents, but also pose a threat as biological weapons. The molecular mechanism leading to their toxic effects is, however, not yet clear. The current paradigm, which states that the irreversible depurination of 28S rRNA results in a general translational arrest eventually leading to cell death, has been questioned. Using micro-array, qRT-PCR and Western blot, we identified the unfolded protein response (UPR), a cellular mechanism activated in response to endoplasmic reticulum stress, that is induced in HCT116 and MDA-MB-231 cells exposed to the plant type II RIPs ricin, riproximin and volkensin. Apoptosis was induced by concentrations at which translation of UPR-related genes still occurred, despite concomitant ribosomal depurination. We conclude that UPR induction represents a model that better describes the cellular effects of RIP exposure at concentrations at which selected proteins are translated despite ribosomal depurination.
    Type of Publication: Journal article published
    PubMed ID: 20844919
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  • 10
    Keywords: CANCER ; CELLS ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; Germany ; CLASSIFICATION ; incidence ; liver ; NEW-YORK ; SAMPLE ; SAMPLES ; transcription ; TISSUE ; PATIENT ; primary ; TISSUES ; LYMPH-NODES ; MR ; bone marrow ; BONE-MARROW ; score ; STAGE ; ASSAY ; DIFFERENCE ; METASTASIS ; colorectal cancer ; COLORECTAL-CANCER ; chemotherapy ; MARKERS ; EPITHELIAL-CELLS ; CANCER-PATIENTS ; CARCINOEMBRYONIC ANTIGEN ; CARCINOMAS ; COLORECTAL CARCINOMAS ; CYTOKERATIN-20 ; DISSEMINATED TUMOR-CELLS ; dissemitiated tumor cells (DTC),hematogenic and lymphatic spread,RT-PCR detection of epithelial mark ; INVOLVEMENT ; MICROMETASTASES ; PERIPHERAL VENOUS-BLOOD ; POLYMERASE-CHAIN-REACTION ; PROGNOSTIC FACTORS ; PROGNOSTIC-SIGNIFICANCE ; RT-PCR
    Abstract: The aim of our prospective study was to detect circulating epithelial cells (CEC) indicating the presence of disseminated tumor cells (DTC) in tissues affected by lymphatic and hematogenic colorectal cancer metastasis. DTC were tracked in lymph node, liver or bone marrow samples of 245 colorectal cancer patients using 2 independent RT-PCR assays for cytokeratin 20 (CK20) and guanylylcyclase C (GCC) that demonstrated a sensitivity of 1 colorectal cancer cell in 10(6) nucleated hematopoietic cells. CK20 mRNA was detected in 79% of lymph nodes, 35% of both liver lobes and 11% of bone marrow samples. GCC mRNA was found in 68% of lymph nodes, 60% of both liver lobes and 6% of bone marrow specimens. Both markers were recorded in 63% of lymph nodes, 45% of at least 1 liver lobe and 1% of bone marrow samples. There was no significant difference when comparing lymph node samples tested positive for both markers in patients with (N1/2; 65%) and without (N0; 56%) nodal involvement. The same was true when comparing the percentages of patients with and without clinically overt distant metastasis who were positive for both markers in at least 1 liver lobe (62% vs. 41%) or in bone marrow (41% vs. 0%). A score denoting the cumulative sum of tests indicating presence of CK20 and GCC mRNA in the liver was significantly related with UICC classification (p = 0.039). However, addition of lymph node results to this score decreased the correlation. The high incidence of clinically inconspicuous lymph node and liver samples tested positive for both markers emphasizes the function of these organs as primary filters for epithelial cells possibly shed from colorectal carcinomas. The potential prognostic significance of these findings warrants verification, especially regarding the importance of CEC or DTC resident in the liver of collorectal cancer patients. (C) 2003 Wiley-Liss
    Type of Publication: Journal article published
    PubMed ID: 14520701
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