ABSTRACT
BACKGROUND: Mesna is a sulfohydrate administered as a supportive drug in conjunction with oxazaphosphorines to prevent bladder toxicity from metabolites. When oxazaphosphorines are given simultaneously with platinum drugs, Mesna binds with platinum drugs as well. Previously we showed in cell culture, that Mesna reduces the efficacy of some platinum drugs. Here we elucidate the chemical reaction mechanism. MATERIAL AND METHODS: Cisplatin, Carboplatin and a novel platinum agent Oxiplatin were incubated with Mesna and the rate of disappearance of Mesna was measured, using an oxidation/reduction reaction between MTT and Mesna. RESULTS: All three platinum agents reacted with Mesna, but the chemical details differed largely. The molar ratios were 3:1, 2:1, and 1:1 for the reactions of Mesna with Oxiplatin, Cisplatin, and Carboplatin, respectively. The speed of the reaction followed a similar pattern, being fastest for Oxiplatin and slowest for Carboplatin. CONCLUSION: When considering the pharmacokinetics of Mesna and these platinum compounds and their reactivity, it appears unlikely that the reaction of Mesna with Carboplatin will become clinically relevant, while Cisplatin, might react with Mesna in patient serum.
Subject(s)
Antineoplastic Agents/chemistry , Carboplatin/chemistry , Cisplatin/chemistry , Mesna/chemistry , Organoplatinum Compounds/chemistry , Platinum Compounds/chemistry , Pyridines/chemistry , Calibration , Kinetics , Molecular StructureABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Benzimidazoles/chemical synthesis , Cisplatin/pharmacology , Cross-Linking Reagents/pharmacology , Organoplatinum Compounds/chemical synthesis , Antineoplastic Agents/chemical synthesis , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Brain Neoplasms/pathology , Chemical Phenomena , Chemistry, Physical , Cisplatin/chemistry , Cross-Linking Reagents/chemical synthesis , DNA Repair/genetics , Drug Design , Drug Resistance, Neoplasm/genetics , Drug Screening Assays, Antitumor , Fibroblasts/drug effects , Glioma/pathology , Humans , Medulloblastoma/pathology , Molecular Structure , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacology , Structure-Activity Relationship , Tumor Cells, Cultured/drug effectsABSTRACT
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.
