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Biomedical subjects

B Krebs

Publications and source records attributed to B Krebs.

119 records · Page 7Linked to original sources
PubMedDate not supplied

Overcoming cisplatin resistance: design of novel hydrophobic platinum compounds.

BACKGROUND: The anticancer activity of cisplatin derives from its ability to crosslink DNA. Cisplatin-resistance is partially caused by enhanced nucleotide excision repair (NER). Major 1,2-intrastrand crosslinks can create a hydrophobic notch at the damage site, which can be specifically bound by damage-recognition proteins, thus shielded from NER-activity. We aimed at preventing resistance by enhancing this mechanism using more hydrophobic platinum compounds. METHODS: We synthesized three platinum analogs with increased hydrophobic characteristics. Performing MTT-assays, the efficacy of cisplatin and the novel agents was compared in a fibroblast and eight brain tumour cell lines. RESULTS: Among the novel compounds, the most hydrophobic molecule, methylpyridineplatinum, was most cytotoxic (LC50 = 5.84 x 10(-5) M), followed by methylpyrazineplatinum, the second most hydrophobic (LC50 = 1.79 x 10(-4) M), and pyridineplatinum (LC50 = 2.76 x 10(-4) M). Overall, cisplatin revealed highest cytotoxicity (LC50 = 8.77 x 10(-6) M). CONCLUSIONS: Comparison of the novel compounds supports the hypothesis that increased hydrophobicity contributes to higher antitumour-activity. Other advantageous characteristics of cisplatin might relate to its remaining highest efficacy.

Antineoplastic Agents↗
PubMedDate not supplied

Rational design of platinum chemotherapeutic drugs: hydrophobicity increases cytotoxicity.

BACKGROUND: Malignant glioma are often resistant to cisplatin. Numerous chemical modifications have been made to overcome this limitation. Analyzing such novel compounds, we previously hypothesized, that hydrophobicity improves the cytotoxicity of NH3 substituted platinum agents. MATERIALS AND METHODS: Testing this hypothesis, we synthesized further eight novel platinum agents, substituting the NH3 groups with various pyridyl ring systems. The cytotoxicity was measured in MTT tests using the cisplatin resistant human U25 1 malignant glioma cell line as a model. Solubility was measured in water using flameless atomic absorption spectroscopy. RESULTS: Cytotoxicity correlated significantly with low water solubility. The relation of cells surviving 72-hours of 1 OuM drug exposure was best described by a logarithmic formula: Surviving cells (% of control) = 6.4 + 38.4 log (water solubility in mg Pt/L) Adding an oximgroup to the aromatic substitute decreased cytotoxicity. CONCLUSIONS: These data confirmed that increased hydophobicity increases cytotoxicity in this group. This might be caused by better cellular penetration, or by shielding of DNA-adducts from repair processes. The data created a further hypothesis: A positive mesomeric effect as characteristic for the oxim-group might decrease DNA binding, a negative mesomeric might improve it.

Antineoplastic Agents↗
PubMedDate not supplied

Cellular accumulation determines the activity of three novel tricyclic platinum agents.

BACKGROUND: Cisplatin (CDDP) is a very useful chemotherapeutic agent, but cellular resistance limits its efficacy in malignant glioma. In order to analyze and overcome this resistance, we synthesized three novel platinum compounds; aminoplatin, methylplatin and oxiplatin, using tricyclic DNA intercalating molecules as models. MATERIALS AND METHODS: The novel compounds differ only in one chemical group, which is positioned opposite to the DNA binding site. DNA binding, cellular penetration, and cytotoxicity were compared in three human glioma cell lines (T98G, U87-MG, and U25 IN) and a human fibroblast cell strain (HS 68). 2 RESULT: Binding to isolated DNA was most effective in aminoplatin, followed by methylplatin and oxiplatin. It differed by factors I. I, 0.35, 0.23, from the DNA binding of CDDP (factor I) for the three compounds, respectively. The cellular penetration, however, was fastest with oxiplatin (factor 10.1) followed by CDDP (1), aminoplatin (0.55), and methylplatin (0.27). The cytotoxicity of the three novel compounds followed the pattern of their cellular penetration with oxiplatin being the most active. U87-MG cells were resistant to CDDP, and in this cell line oxiplatin was more effective than CDDP in overcoming the resistance. CONCLUSION: This indicates cellular penetration to be an important feature and the ketogroup of oxiplatin to be beneficial in tricyclic platinum compounds.

Aminopyridines↗