ABSTRACT
PURPOSE: The Auger emitting isotope 123I has a much shorter half-life (13.2 hours), than 125I, the prototype Auger emitter. Monte Carlo simulations and cell culture studies indicate that decay of 123I covalently incorporated into DNA is about half as effective as 125I in terms of DNA breakage and cytotoxicity. The aim of the present study is to assess the DNA breakage efficacy of 123I that is non-covalently associated with DNA, using the minor groove binding ligand iodoHoechst 33258. MATERIALS AND METHODS: Plasmid (pBR322) DNA was incubated with mixtures of [123I]- and [125I]-iodoHoechst 33258, and DNA double strand breakage (DSB) assessed by assaying the relative amounts of intact, relaxed and linear plasmid forms separated by agarose gel electrophoresis. This "double-label" approach provides a measure of the ratio of probabilities of DSB formation per decay for these two isotopes, with much higher precision than comparing the absolute probabilities for the individual isotopes, principally because it avoids the requirement to accurately determine the fraction of bound ligand. RESULTS: Our results indicate that the ratio of DSB probability per decay of 123I to that of 125I is 0.63 +/- 0.03. The ratio does not change much with addition of dimethyl sulfoxide (DMSO) to the incubation mixture--0.65 +/- 0.03. This ratio agrees well with the relative efficiency of the two isotopes reported in theoretical and experimental studies, using various endpoints. CONCLUSIONS: In considering the possible exploitation of the Auger effect in cancer therapy, the modest decrease in DNA breakage efficacy for 123I compared to 125I might be more than compensated for by the advantage of the much shorter half-life. The 60-day half-life of 125I imposes severe limitations in terms of radiation protection.
Subject(s)
Bisbenzimidazole/analogs & derivatives , Bisbenzimidazole/adverse effects , DNA Damage , Electrons , Iodine Radioisotopes/adverse effects , Models, Chemical , Plasmids/chemistry , Plasmids/radiation effects , Computer Simulation , Dose-Response Relationship, Radiation , Half-Life , Linear Energy Transfer , Models, Statistical , Radiation Dosage , Relative Biological EffectivenessABSTRACT
Pibenzimol is a fluorescent molecule known to bind to double stranded DNA. It also induces prolongation of the G2 phase of the cell cycle, inhibition of DNA replication and cessation of the growth of some cells in late S phase after DNA content has been doubled. It has been shown to increase the life span of mice bearing intraperitoneally implanted L1210 and P388 leukemia. These factors coupled with the affinity of pibenzimol for pancreatic tissue led us to conduct a phase I-II trial of pibenzimol hydrochloride in patients with advanced pancreatic cancer. Twenty-six patients were treated with a five day continuous infusion of pibenzimol at a dose ranging from 6-28 mg/m2/d. There were no treatment related deaths. Major toxicity was hyperglycemia which was self-limited. No objective responses were noted.
Subject(s)
Bisbenzimidazole/therapeutic use , Carcinoma, Intraductal, Noninfiltrating/drug therapy , Pancreatic Neoplasms/drug therapy , Adult , Bisbenzimidazole/administration & dosage , Bisbenzimidazole/adverse effects , Bisbenzimidazole/blood , Drug Administration Schedule , Drug Evaluation , Gastrointestinal Diseases/chemically induced , Humans , Hyperglycemia/chemically induced , Infusions, IntravenousABSTRACT
Twenty-three patients with advanced pancreatic adenocarcinoma were treated with Pibenzimol utilizing a daily intravenous schedule for five days. There were no objective responses seen. The major toxicity was pancreatic with grade 3 hyperglycemia in eleven patients. Pibenzimol is inactive in patients with advanced pancreatic adenocarcinoma.
Subject(s)
Adenocarcinoma/drug therapy , Bisbenzimidazole/therapeutic use , Pancreatic Neoplasms/drug therapy , Adult , Aged , Bisbenzimidazole/adverse effects , Drug Evaluation , Humans , Middle AgedABSTRACT
F151 was a potent filaricide against adult Brugia pahangi in cats and jirds. HOE 33258 did not kill adult worms in cats but had a marginal effect on adult worms in the peritoneal cavity of jirds. It was not immediately microfilaricidal in cats but the microfilarial counts of treated cats fell within a few weeks of treatment. The reaction product, or mixture, of these two compounds (V5851 = E) was strongly macrofilaricidal in cats and jirds.
