Biomedical subjects
Publications and source records attributed to N R Jones.
A series of eight novel nitropyrazines has been prepared by oxidation of sulfoximine intermediates. The partition coefficient, one-electron reduction potential, sensitizer enhancement ratio, and chronic and acute aerobic cytotoxicity have been measured for each. Two representatives of this series were tested in the Ames test and were not found to be mutagenic.
When the cellular glutathione content is reduced, adding oxygen (130 mumol dm-3) 7 ms after irradiation of hypoxic cells increases the radiosensitivity (factor approximately 1.25), whereas it has much less effect in normal cells.
A liquid flow rapid-mixing apparatus has been used to study the role of lipophilicity (octanol: water partition coefficient, P) in the sensitization of hypoxic V79 cells by nitroimidazoles. Sensitization by seven neutral 2-nitroimidazoles of similar reduction potential but widely differing partition (0.11-77) and one basic 2-nitroimidazole (pKa=8.9; p=8.5 (of free base)) was studied as a function of pre-irradiation contact time ca. 3-40 ms. With increasing P, sensitization occurs at increasingly shorter pre-irradiation contact times. The results suggest that even though factors other than passive diffusion control the sensitization observed with the base Ro 03-8799 it is able to diffuse to the target site faster than midonidazole.
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Some chemical and biological properties of intermediates obtained during reduction of nitroimidazoles are discussed. These include: rate data for the decay of the nitro radical-anion, stoichiometry and absorption spectra for reduction via the radical-anion or using dithionite, stoichiometry with other reducing agents, and rate of reduction by xanthine/xanthine oxidase. Increased radiosensitization by misonidazole is seen upon prolonged pre-irradiation incubation using E. coli, enabling demonstration that a freely-diffusable metabolite is responsible for this effect. Preliminary experiments designed to extend studies of the radiobiological properties of extracellularly-added metabolites to mammalian cells and the use of liver perfusion to generate metabolites are described.
Previous studies have demonstrated decreased levels of DNA topoisomerase II alpha protein and messenger RNA in the Adriamycin-resistant P388 murine leukemia cell line P388/ADR/7 compared to the sensitive P388/4 cell line. An allelic fusion event involving the topoisomerase II alpha and the retinoic acid receptor a genes has been identified in these cells that probably contributes to the decreased topoisomerase II activity in P388/ADR/7 cells. However, this allelic mutation may be a minor contributor or even incidental to the resistance phenotype, since these cells display other candidate mechanisms of resistance, including increased P-glycoprotein, increased glutathione-S-transferase activity and an increased onset of DNA repair. To establish a role for topoisomerase II alpha in mediating the Adriamycin resistance phenotype, complementation of the mutant allele was attempted by transfecting the murine P388/ADR/7 cells with a human topoisomerase II alpha expression construct under the control of the human metallothionein IIA promoter. The majority of transfected cell lines that were obtained by selection in hygromycin B contained copies of the integrated expression construct that were rearranged. Only two of thirty-two transfected cell lines were found to contain a single, unrearranged copy of the human topoisomerase II alpha cDNA. P388/ADR/7 cell lines carrying an integrated, intact human topoisomerase II alpha expression vector were more sensitive to Adriamycin, daunorubicin, mitoxantrone, and etoposide, but not to actinomycin D and vincristine compared to control cells transfected with vector alone or cell lines with rearranged topoisomerase II alpha expression constructs. These findings suggest that topoisomerase II alpha is a selective and significant contributor to multifactorial resistance.