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| 2. |
- Dreilich, Martin, et al.
(author)
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Telomerase activity is not a key determinant of sensitivity to standard cytotoxic drugs in human esophageal carcinoma cell lines
- 2006
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In: Anti-Cancer Drugs. - 0959-4973 .- 1473-5741. ; 17:5, s. 503-509
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Journal article (peer-reviewed)abstract
- The aim of the present study was to investigate if basal telomerase activity levels may predict sensitivity to cytotoxic drugs in a panel of human esophageal carcinoma cell lines. The TRAPeze telomerase detection assay was used to investigate telomerase activity in the cell lines. Cytotoxic drug sensitivity for 20 standard cytotoxic agents was assessed using the fluorometric microculture cytotoxicity assay (FMCA). Telomerase activity was detected in all cell lines with a broad range of activity levels. Drug sensitivity also varied considerably between the cell lines. Except for a P value towards a correlation between mitoxantrone and telomerase activity (P=0.054), no statistically significant correlation was found between telomerase activity levels and sensitivity to investigated drugs, including key drugs such as cisplatin (P=0.9), 5-fluorouracil (P=0.8) and doxorubicin (P=0.54). We therefore conclude that basal telomerase activity level is not a key determinant of sensitivity to standard cytotoxic drugs in esophageal carcinoma cell lines.
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| 3. |
- Engman, Lars, et al.
(author)
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Thioredoxin reductase and cancer cell growth inhibition by organogold(III) compounds
- 2006
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In: Anti-Cancer Drugs. - 0959-4973 .- 1473-5741. ; 17:5, s. 539-544
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Journal article (peer-reviewed)abstract
- Thioredoxin (Trx) expression is increased in several human primary cancers associated with aggressive tumor growth and decreased patient survival, and the Trx/Trx reductase (TrxR) system therefore provides an attractive target for cancer drug development. Various gold(III) compounds with none, one, two or three carbon-gold bonds were evaluated for their capacity to inhibit TrxR and the growth of MCF-7 cancer cells in vitro. Compounds with up to two carbon-gold bonds were often potent inhibitors of TrxR with IC50 values as low as 2 nmol/l. In the presence of Trx and insulin the inhibiting capacity was much lower. However, the inhibitory concentrations of the compounds did not correlate with the ability to kill cells. Out of the organometallics tested, only compound 8 with two carbon-gold bonds was able to inhibit colony formation by MCF-7 breast cancer cells at low micromolar concentrations (IC50=1,6umol/l). Unfortunately, the compound did not show any anti-tumor activity against MCF-7 breast cancer and HT-29 colon cancer zenografts in scid mice.
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| 4. |
- Hallböök, Helene, et al.
(author)
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In vitro activity of imatinib in cells from patients with adult acute lymphoblastic leukemia
- 2005
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In: Anti-Cancer Drugs. - 0959-4973 .- 1473-5741. ; 16:6, s. 631-634
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Journal article (peer-reviewed)abstract
- We evaluated the in vitro activity of imatinib on BCR-ABL-positive and -negative tumor cells from patients with adult acute lymphoblastic leukemia (ALL), and investigated in vitro interactions between imatinib and conventional agents. A non-clonogenic cytotoxicity assay was used to analyze p190 BCR-ABL-positive (n = 4), p210 BCR-ABL-positive (n = 2) and BCR-ABL-negative (n = 9) tumor cells from adult ALL patients. The in vitro cytotoxic effect of imatinib was studied alone, and in combination with the cytotoxic agents cytarabine, prednisolone, vincristine, daunorubicin, asparaginase and mercaptopurine. The BCR-ABL-positive samples were significantly (p < 0.05) more sensitive to imatinib than the BCR-ABL-negative at the concentrations 0.1, 1 and 10 muM. Interestingly, the two p210 samples were somewhat less sensitive to imatinib than the p190 samples. Daunorubicin, prednisolone and cytarabine showed the largest benefit from combination with imatinib compared to the most active single agent. The study confirms that drug sensitivity to imatinib is specific for BCR-ABL-positive samples. The results also suggest that combinations between imatinib and daunorubicin, predisolone or cytarabine may be advantageous for the treatment of Philadelphia-positive ALL.
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| 5. |
- Holst, Martina, et al.
(author)
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Molecular mechanisms underlying N1, N11-diethylnorspermine-induced apoptosis in a human breast cancer cell line.
- 2008
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In: Anti-Cancer Drugs. - 0959-4973. ; 19:9, s. 871-883
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Journal article (peer-reviewed)abstract
- Polyamine analogue treatment results in growth inhibition and sometimes in cell death. Therefore, polyamine analogues are considered in the treatment of cancer; however, the cellular properties that govern sensitivity are not known. The objective of this study was to elucidate molecular mechanisms behind apoptosis induced by the polyamine analogue N, N-diethylnorspermine (DENSPM). Four different breast cancer cell lines were treated with DENSPM. Cell death was evaluated with flow cytometry and a caspase 3 assay. The levels of a number of proapoptotic and antiapoptotic proteins in subcellular compartments were evaluated with western blot. In the most sensitive cell line, DENSPM treatment induced the release of cytochrome c from mitochondria, resulting in activation of caspase 3 but without decreasing the mitochondrial transmembrane potential. However, in the three other cell lines DENSPM treatment did not induce extensive cell death. This is partly explained by the high levels of antiapoptotic proteins Bcl-2 and Bad and low levels of proapoptotic proteins Bax and procaspase 3 in these three cell lines. The results are also partly explained by the degree of activation of the catabolic enzyme spermidine/spermine-N-acetyltransferase and polyamine pool reduction achieved by DENSPM treatment. Our results show that the protein profile of proapoptotic and antiapoptotic proteins may contribute to the outcome to treatment with the polyamine analogue DENSPM. The results also indicate that it should be possible to find molecular markers for sensitivity to DENSPM that could be used in the clinic to predict sensitivity to a polyamine analogue.
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| 6. |
- Jönsson, Peter, et al.
(author)
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Methotrexate concentrations in cerebrospinal fluid and serum, and the risk of central nervous system relapse in children with acute lymphoblastic leukaemia
- 2007
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In: Anti-Cancer Drugs. - 0959-4973. ; 18:8, s. 941-948
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Journal article (peer-reviewed)abstract
- The aim of the study was to characterize the relationship between the pharmacolkinetics of methotrexate in serum and concentrations in the cerebrospinal fluid, and to analyse the association to risk of a central nervous system relapse in children with acute lymphoblastic leukaemia. In this retrospective study, 353 children with acute lymphoblastic leukaemia treated with high-dose methotrexate according to the Nordic Society of Pediatric Haematology and Oncology-92 acute lymphoblastic leukaemia protocol were studied. Data from 18 patients with a subsequent central nervous system relapse and 335 event-free patients were available. In 34 patients the methotrexate concentrations were monitored repeatedly during each 24-h methotrexate intravenous infusion and a cerebrospinal fluid sample was taken at the end of the infusion. Using statistics separating interindividual and intraindividual variability, methotrexate concentration in cerebrospinal fluid was found to be significantly dependent upon both serum concentrations at the end of infusion and the area under the concentration curve in serum (P<0.0017 and <0.002, respectively). The logistic regression analysis revealed that high patient median serum methotrexate concentrations at the end of infusion were significantly associated with decreased risk for a central nervous system relapse in the standard risk group (P=0.02) and the number of courses with a calculated cerebrospinal fluid concentration of more than 1 mu mol/l (P=0.048) with a decreased risk of a central nervous system relapse in the combined (standard risk and intermediate) risk group. In conclusion, methotrexate concentrations in cerebrospinal fluid are dependent on methotrexate concentrations in serum and serum area under the concentration curve. Multivariate analysis indicates that an increased exposure to methotrexate is related to decreased risk for central nervous system relapse.
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| 7. |
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| 8. |
- Molin, Ylva, et al.
(author)
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Sequential effects of daily arsenic trioxide treatment on essential and nonessential trace elements in tissues in mice
- 2008
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In: Anti-Cancer Drugs. - 0959-4973 .- 1473-5741. ; 19:8, s. 812-8
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Journal article (peer-reviewed)abstract
- Despite arsenic's (As) toxic potential, arsenic trioxide (As2O3) is used as a safe and effective treatment in acute promyelocytic leukaemia. However, it is unknown whether such therapy influences the balance of other trace elements in the body. In this study, mice were treated intraperitoneally daily with 1.0 mg As2O3/kg bw for 3, 5 or 7 days. As, and seven essential and nonessential trace elements with the potential to interact with As, were measured through inductively coupled plasma-mass spectrometry in serum, heart, lung, liver, pancreas, kidney, intestine and brain. As2O3 supplementation increased As in all target tissues on day 3, thereafter reaching an almost steady state. The major findings in other elements were a sequential decrease in serum zinc (on day 7 by 64%; P<0.001), and a decrease in selenium in the pancreas on day 3 (9%; P<0.05), in the intestine on day 3 (30%; P<0.001) and finally, in the brain on days 5 (12%; P<0.05) and 7 (15%; P<0.01). Changes in magnesium, iron, copper, cadmium and mercury were minor and inconsistent. This study suggests that supplementation with other trace elements may be beneficial when As2O3 treatment regimens are used in the clinic.
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| 9. |
- Myhre, Louise, et al.
(author)
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Different cell cycle kinetic effects of N1,N11-diethylnorspermine-induced polyamine depletion in four human breast cancer cell lines.
- 2008
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In: Anti-Cancer Drugs. - 0959-4973. ; 19:4, s. 359-368
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Journal article (peer-reviewed)abstract
- Polyamine analogues are presently undergoing clinical evaluation in the treatment of cancer. To better understand under what circumstances treatment with a polyamine analogue will yield beneficial results, we have investigated the effect of N,N-diethylnorspermine (DENSPM) on cell cycle kinetics of the human breast cancer cell lines SK-BR-3, MCF-7, HCC1937, and L56Br-C1. A bromodeoxyuridine-DNA flow cytometry method was used to evaluate the treatment with 10 micromol/l DENSPM on cell cycle kinetics. A correlation between polyamine pool size after DENSPM treatment and cell cycle kinetic effects was found. The most sensitive cell cycle phase was the S phase, followed by an effect on the G2+M phase and then the G1/S transition. The levels of a number of cell cycle regulatory proteins such as cyclin E1, cyclin A2, and cyclin B1 were lowered by DENSPM treatment, which may explain the effects on cell cycle kinetics. The two cell lines that were most sensitive to DENSPM treatment belong to the basal-like subtype of breast cancer and they were deficient with respect to p53, BRCA1, and RB1.
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| 10. |
- Myhre, Louise, et al.
(author)
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Normal-like breast cells, but not breast cancer cells, recovered from treatment with N ',N ''-diethylnorspermine
- 2009
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In: Anti-Cancer Drugs. - 0959-4973. ; 20:4, s. 230-237
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Journal article (peer-reviewed)abstract
- A number of polyamine analogs are currently used in various clinical trials as cancer treatment and it is important to investigate their effects not only on cancer cells but also on normal cells. Treatment with polyamine analogs depletes cells of polyamines and inhibits cell proliferation, but the analogs cannot take over the normal function of the natural polyamines in the cell. In this study, the normal-like breast epithelial cell line MCF-10A was treated with the polyamine analog N',N ''-diethylnorspermine (DENSPM). The cells were then studied using a bromodeoxyuridine-DNA flow cytometry method as well as western blot. The ability of both normal-like and breast cancer cells to recover from DENSPM treatment was also studied. DENSPM treatment of MCF-10A cells resulted in a prolongation of the S and G(2) + M phases, followed by a G(1)/S block. The p53/p21/RB1 pathway was involved in the G(1)/S block as shown by increased levels of p53 and p21 detected by western blot. Decreased levels of cyclin E1, cyclin A2, and cyclin B1 in DENSPM-treated cells can explain the prolongation of cell cycle phases that occurred before the G(1)/S block. We also show that MCF-10A cells rapidly recover from DENSPM-induced growth inhibition in contrast to four human breast cancer cell lines. The goal of cancer treatment is to cause minimal and reversible damage to normal cells, while cancer cells should be eliminated. Altogether, the data show that treatment with polyamine analogs spares normal cells, while negatively affecting the cancer cells. Anti-Cancer Drugs 20:230-237 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.
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