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| 2. |
- Ekman, Simon, et al.
(författare)
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Clinical value of using serological cytokeratins as therapeutic markers in thoracic malignancies
- 2007
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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 27:5B, s. 3545-3553
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Forskningsöversikt (refereegranskat)abstract
- In recent years, there has been an increasing awareness among physicians of the value of therapeutic interventions in patients suffering from lung cancer and mesothelioma. A search for an optimal approach using surgery, irradiation and chemotherapy in different settings of the tumour disease, including curatively aimed adjuvant chemotherapy after locoregional surgery or radiotherapy, has resulted in gradually improved survival rates. Still, early detection is crucial if there is to be a possibility of curing patients or prolonging life in cases of relapsed disease. Several studies have been initiated in which surrogate markers are evaluated in comparison to chest X-rays and computer tomography. The present review focuses on the predictive and prognostic value of using serological cytokeratins as tumour markers for patients suffering from thoracic malignancies.
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| 3. |
- Felth, Jenny, et al.
(författare)
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Cytotoxic effects of cardiac glycosides in colon cancer cells, alone and in combination with standard chemotherapeutic drugs
- 2009
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Ingår i: Journal of natural products (Print). - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 72:11, s. 1969-1974
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Tidskriftsartikel (refereegranskat)abstract
- Cardiac glycosides have been reported to exhibit cytotoxic activity against several different cancer types, but studies against colorectal cancer are lacking. In a screening procedure aimed at identifying natural products with activity against colon cancer, several cardiac glycosides were shown to be of interest, and five of these were further evaluated in different colorectal cancer cell lines and primary cells from patients. Convallatoxin (1), oleandrin (4), and proscillaridin A (5) were identified as the most potent compounds (submicromolar IC50 values), and digitoxin (2) and digoxin (3), which are used in cardiac disease, exhibited somewhat lower activity (IC50 values 0.27−4.1 μM). Selected cardiac glycosides were tested in combination with four clinically relevant cytotoxic drugs (5-fluorouracil, oxaliplatin, cisplatin, irinotecan). The combination of 2 and oxaliplatin exhibited synergism including the otherwise highly drug-resistant HT29 cell line. A ChemGPS-NP application comparing modes of action of anticancer drugs identified cardiac glycosides as a separate cluster. These findings demonstrate that such substances may exhibit significant activity against colorectal cancer cell lines, by mechanisms disparate from currently used anticancer drugs, but at concentrations generally considered not achievable in patient plasma.
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| 4. |
- Fryknäs, Mårten, et al.
(författare)
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Phenotype-based screening of mechanistically annotated compounds in combination with gene expression and pathway analysis identifies candidate drug targets in a human squamous carcinoma cell model
- 2006
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Ingår i: Journal of Biomolecular Screening. - : Elsevier BV. - 1087-0571 .- 1552-454X. ; 11:5, s. 457-468
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Tidskriftsartikel (refereegranskat)abstract
- The squamous cell carcinoma HeLa cell line and an epithelial cell line hTERT-RPE with a nonmalignant phenotype were interrogated for HeLa cell selectivity in response to 1267 annotated compounds representing 56 pharmacological classes. Selective cytotoxic activity was observed for 14 of these compounds dominated by cyclic adenosine monophosphate (cAMP) selective phosphodiesterase (PDE) inhibitors, which tended to span a representation of the chemical descriptor space of the library. The PDE inhibitors induced delayed cell death with features compatible with classical apoptosis. The PDE inhibitors were largely inactive when tested against a cell line panel consisting of hematological and nonsquamous epithelial phenotypes. In a genome-wide DNA microarray analysis, PDE3A and PDE2A were found to be significantly increased in HeLa cells compared to the other cell lines. The pathway analysis software PathwayAssist was subsequently used to extract a list of proteins and small molecules retrieved from Medline abstracts associated with the hit compounds. The resulting list consisted of major parts of the cAMP-protein kinase A pathway linking to ERK, P38, and AKT. This molecular network may provide a basis for further exploitation of novel candidate targets for the treatment of squamous cell carcinoma.
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| 5. |
- Herrmann, Anders, et al.
(författare)
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Key role of glutamic acid for the cytotoxic activity of the cyclotide cycloviolacin O2
- 2006
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Ingår i: Cellular and Molecular Life Sciences (CMLS). - : Springer Science and Business Media LLC. - 1420-682X .- 1420-9071. ; 63:2, s. 235-245
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Tidskriftsartikel (refereegranskat)abstract
- Cyclotides are cyclic plant proteins with potent cytotoxic effects. Here we systematically probed the importance of surface-exposed charged amino acid residues of the cyclotide cycloviolacin O2, using a strategy involving chemical modifications. We show that the single glutamic acid plays a key role for the cytotoxicity: methylation of this residue produced a 48-fold decrease in potency. Virtually no change in potency was observed when masking the single arginine residue using 1,2-cyclohexanedione, while acetylation of the two lysine residues reduced the potency 3-fold. The derivative with modifications at both arginine and lysine residues showed a 7-fold loss of potency. In addition, we show that the activity is dependent on an intact disulfide network and that the short sequences between the six cysteine residues, that is, the backbone loops, are devoid of cytotoxic activity.
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| 6. |
- Herrmann, Anders, et al.
(författare)
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The alpine violet, Viola biflora, is a rich source of novel cyclotides with potent cytotoxic cytotoxicity
- 2008
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Ingår i: Phytochemistry. - : Elsevier BV. - 0031-9422 .- 1873-3700. ; 69:4, s. 939-952
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Tidskriftsartikel (refereegranskat)abstract
- The cyclotides are currently the largest known family of head-to-tail cyclic proteins. The complex structure of these small plant proteins, which consist of approximately 30 amino acid residues, contains both a circular peptide backbone and a cystine knot, the combination of which produces the cyclic cystine knot motif. To date, cyclotides have been found in plants from the Rubiaceae, Violaceace and Cucurbitaceae families, and are believed to be part of the host defence system. In addition to their insecticidal effect, cyclotides have also been shown to be cytotoxic, anti-HIV, antimicrobial and haemolytic agents. In this study, we show that the alpine violet Viola biflora (Violaceae) is a rich source of cyclotides. The sequences of 11 cyclotides, vibi A-K, were determined by isolation and MS/MS sequencing of proteins and screening of a cDNA library of V. biflora in parallel. For the cDNA screening, a degenerate primer against a conserved (AAFALPA) motif in the cyclotide precursor ER signal sequence yielded a series of predicted cyclotide sequences that were correlated to those of the isolated proteins. There was an apparent discrepancy between the results of the two strategies as only one of the isolated proteins could be identified as a cDNA clone. Finally, to correlate amino acid sequence to cytotoxic potency, vibi D, E, G and H were analysed using a fluorometric microculture cytotoxicity assay using a lymphoma cell line. The IC50-values of the bracelet cyclotides vibi E, G and H ranged between 0.96 and 5.0 mu M while the Mobius cyclotide vibi D was not cytotoxic at 30 mu M.
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| 9. |
- Lövborg, Henrik, et al.
(författare)
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Structure-activity relationship analysis of cytotoxic cyanoguanidines : selection of CHS 828 as candidate drug.
- 2009
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Ingår i: BMC research notes. - : Springer Science and Business Media LLC. - 1756-0500. ; 2, s. 114-
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: N-(6-(4-chlorophenoxy)hexyl)-N'-cyano-N''-4-pyridyl guanidine) (CHS 828) is the first candidate drug from a novel group of anti-tumour agents - the pyridyl cyanoguanidines, shown to be potent compounds interfering with cellular metabolism (inhibition of nicotinamide phosphoribosyl transferase) and NF-kappaB signalling. Substituted cyanoguanidines are also found in anti-hypertensive agents such as the potassium channel opener pinacidil (N-cyano-N'-(4-pyridyl)-N''-(1,2,2-trimethylpropyl)guanidine) and histamine-II receptor antagonists (e.g. cimetidine, N-cyano-N'-methyl-N''-[2-[[(5-methylimidazol-4-yl]methyl]thio]ethyl)guanidine). In animal studies, CHS 828 has shown very promising activity, and phase I and II studies resulted in further development of a with a water soluble prodrug. FINDINGS: To study the structural requirements for cyanoguanidine cytotoxicity a set of 19 analogues were synthesized. The cytotoxic effects were then studied in ten cell lines selected for different origins and mechanisms of resistance, using the fluorometric microculture cytotoxicity assay (FMCA). The compounds showed varying cytotoxic activity even though the dose-response curves for some analogues were very shallow. Pinacidil and cimetidine were found to be non-toxic in all ten cell lines. Starting with cyanoguanidine as the crucial core it was shown that 4-pyridyl substitution was more efficient than was 3-pyridyl substitution. The 4-pyridyl cyanoguanidine moiety should be linked by an alkyl chain, optimally a hexyl, heptyl or octyl chain, to a bulky end group. The exact composition of this end group did not seem to be of crucial importance; when the end group was a mono-substituted phenyl ring it was shown that the preferred position was 4-substitution, followed by 3- and, finally, 2-substitution as the least active. Whether the substituent was a chloro, nitro or methoxy substituent seemed to be of minor importance. Finally, the activity patterns in the ten cell lines were compared. Substances with similar structures correlated well, whilst substances with large differences in molecular structure demonstrated lower correlation coefficients. CONCLUSION: According to this structure-activity relationship (SAR) study, CHS 828 meets the requirements for optimal cytotoxic activity for this class of compounds.
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