Shinde, S. S.; Anderson, R. F.; Lobachevsky, P.; Martin, R. F.
Funding organisation: Australian Institute of Nuclear Science and Engineering, Lucas Heights, NSW (Australia)
Insights into barrier-controlled hole migration in DNA2006
Funding organisation: Australian Institute of Nuclear Science and Engineering, Lucas Heights, NSW (Australia)
Insights into barrier-controlled hole migration in DNA2006
AbstractAbstract
[en] Full text: The mechanism by which charges migrate in DNA continues to be an area of active fundamental research. We have used bibenzimidazole ligands, which bind tightly to the minor groove of DNA, to study the migration of electron deficient centers produced by abstraction of an electron from DNA bases, using the pulse radiolysis technique, in aqueous solution at ambient temperature. Formation of one-electron oxidized ligands by migration of the hole is monitored by time-resolved spectrophotometry, at various ligand/DNA base ratios. These studies build on our previous work with methylpromine and Hoechst 33342 to include a series of ligands which possess both electron donating and withdrawing substituents on the terminal benzene ring. By establishing redox equilibria with promethazine, which binds only weakly to DNA, it has been possible to measure the one-electron reduction potentials, E(1)R, of the DNA-bound ligand radicals for comparison with E(1)R values for the unbound ligands. In all cases E(1)R values are found to increase upon binding of the ligands to DNA. The extent of hole migration along DNA is found to correlate with the rate of electron transfer, a process which is activation energy-controlled
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Australian Institute of Nuclear Science and Engineering, Lucas Heights, NSW (Australia); 72 p; 2006; p. 47; Radiation 2006; Sydney, NSW (Australia); 20-21 Apr 2006; Available in abstract form only, full text entered in this record. Also available from AINSE, Lucas Heights, NSW 2234 (AU)
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Lobachevsky, P. N.; Karagiannis, T. C.; Martin, R. F.
Biological effects of decay of DNA-associated iodine-1232006
Biological effects of decay of DNA-associated iodine-1232006
AbstractAbstract
[en] Full text: Decay of Auger electron emitting isotopes such as 123I and 125I results in high local energy deposition. When such an event occurs in association with DNA it induces cytotoxic DNA damage that makes it possible to exploit Auger-emitters in radioimmunotherapy. The efficiency of induction of cytotoxic lesions by decay of DNA-associated 125I, the prototype Auger-emitter, is well established, but its long half-life (60 days) is a limitation. A much shorter half-life (13.2 hours) of another Auger emitting iodine isotope, 123I is an obvious advantage. However decay of 123I generates an average of 8 - 11 Auger electrons compared to about 15 - 21 electrons for 125I, so the efficiency of DNA damage and subsequent cytotoxicity might be somewhat lower for 123I. We investigated the biological consequences of decay of DNA-associated 123I using breakage of plasmid DNA and clonogenic survival of cultured cells following incubation with DNA binding ligand 123I-iodoHoechst 33258, as endpoints. The efficiency of double strand break induction in pBR 322 plasmid by decay of 123I was 0.62, compared to 0.82 per decay of 125I in the same experimental system. In the presence of dimethylsulfoxide, the values were 0.54 and 0.65 for decay of 123I and 12'5I respectively. Clonogenic survival studies with K562 cells demonstrated that about 370 - 430 decays of 123I per cell constitute a lethal event, compared to130-140 decays of 125I per cell. In considering the possible exploitation of the Auger effect in cancer therapy, the modest decrease in DNA breakage and cytotoxic efficiency of 123I might be compensated for by the advantages of the much shorter half life
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Australian Institute of Nuclear Science and Engineering, Lucas Heights, NSW (Australia); 72 p; 2006; p. 20; Radiation 2006; Sydney, NSW (Australia); 20-21 Apr 2006; Available in abstract form only, full text entered in this record. Also available from AINSE, Lucas Heights, NSW 2234 (AU)
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BETA DECAY RADIOISOTOPES, CELL CONSTITUENTS, DAYS LIVING RADIOISOTOPES, DECAY, DOSES, DRUGS, ELECTRON CAPTURE RADIOISOTOPES, EVALUATION, HOURS LIVING RADIOISOTOPES, IMMUNOTHERAPY, INTERMEDIATE MASS NUCLEI, INTERNAL CONVERSION RADIOISOTOPES, IODINE ISOTOPES, ISOTOPES, LETHAL DOSES, MEDICINE, NUCLEAR MEDICINE, NUCLEI, ODD-EVEN NUCLEI, RADIATION DOSES, RADIOISOTOPES, RADIOLOGY, RADIOTHERAPY, THERAPY
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Martin, R. F.; Smith, A.; Lobachevsky, P.; Karagiannis, T; Leung, B.; Andrau, L.; White, J.
Overview of methylproamine, a new DNA binding radioprotector2006
Overview of methylproamine, a new DNA binding radioprotector2006
AbstractAbstract
[en] Full text: Methylproamine is the current lead compound of a new class of DNA-binding radioprotectors being developed in the Research Laboratories at the Peter MacCallum Cancer Centre in Melbourne. The salient features of methylproamine are its radioprotective potency and the generic nature of the apparent radioprotective mechanism. Like the 'classic' aminothiol radioprotectors exemplified by amifostine, methylproamine suppresses the initial radiochemical damage induced in DNA by ionising radiation. However, survival curve studies with cultured cells have demonstrated that methylproamine is 100-fold more potent than WR1065, the active metabolite of amifostine. The radioprotective mechanism seems to involve reduction by the DNA-bound drug of transient radiation-induced oxidising species on DNA. This mechanism implies some electron transfer along DNA, from the DNA-bound drug to the oxidising species. In vivo radioprotection of mouse lung, GI tract and bone marrow has been demonstrated following systemic administration of methylproamine to mice. The commercial potential of radioprotectors resides in two distinct arenas. Until recently, most of our efforts have focused on the use of methylproamine to protect normal tissues in cancer radiotherapy patients, but a quite different opportunity arises from the imperative to develop countermeasures to the threat of radiation terrorism. Our prospects in both arenas have been lifted by the results of synthesis and screening of a pilot library of ∼50 methylproamine analogues, promising the emergence of new lead drugs. In particular, although methylproamine is a potent radioprotector, at higher concentrations it becomes cytotoxic, but one member of the pilot library shows a wider efficacy 'window'. We plan to continue this lead optimisation process by synthesis and screening of a much larger library of analogues, and we are seeking the support of a commercial partner
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Australian Institute of Nuclear Science and Engineering, Lucas Heights, NSW (Australia); 72 p; 2006; p. 17; Radiation 2006; Sydney, NSW (Australia); 20-21 Apr 2006; Available in abstract form only, full text entered in this record. Also available from AINSE, Lucas Heights, NSW 2234 (AU)
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