Mechanistic studies of the cytotoxic action of selected azonafide analogs
dc.contributor.advisor | Dorr, Robert T. | en_US |
dc.contributor.author | Mayr, Craig, Andrew, 1968- | |
dc.creator | Mayr, Craig, Andrew, 1968- | en_US |
dc.date.accessioned | 2013-04-18T09:50:28Z | |
dc.date.available | 2013-04-18T09:50:28Z | |
dc.date.issued | 1997 | en_US |
dc.identifier.uri | http://hdl.handle.net/10150/282529 | |
dc.description.abstract | The cytotoxic mechanism of selected anthracene-containing, DNA-intercalating antitumor agents (azonafides) was investigated. The hypothesis tested was that these compounds kill tumor cells via poisoning DNA topoisomerase II (TOPO II). This hypothesis was based on observations that similar DNA intercalators poison TOPO II as a contributing mechanism to their cytotoxicity. The agents studied had nuclear effects similar to other DNA intercalators. The azonafides inhibited DNA and RNA synthesis with lesser effects on protein synthesis. They produced DNA damage consistent with TOPO II poisoning, including single strand breaks, double strand breaks and DNA/protein crosslinks. Of the five analogs studied, the two with the greatest cytotoxic potency produced less DNA damage than the other analogs. Furthermore, the DNA damage produced by these two highly toxic analogs did not correlate with their cytotoxic potencies whereas the DNA damage production by the less toxic analogs did. This observation suggests that there may be disparate mechanisms of toxicity among the azonafides. All analogs studied inhibited the activity of purified TOPO II. However, there was no evidence of TOPO II poisoning in these experiments. Intracellular TOPO II poisoning assays revealed that only two of the five analogs poisoned TOPO II. This suggests that TOPO II poisoning is involved in the mechanism of action of some azonafide analogs. However, like other DNA intercalators, there may be alternate, possibly novel, mechanisms involved in their toxicity. Additional studies investigated the effect of metabolism on the activity of the parent compound (azonafide). Four metabolites resulting from in vitro metabolism of azonafide were identified including two desmethyl species, an N-oxide metabolite and a carboxylic acid metabolite. The two desmethyl species retained cytotoxic activity and inhibited TOPO II, but were less potent than the parent. The N-oxide and carboxylic acid metabolites were inactive in cytotoxicity analyses. These findings show that metabolism of azonafide represents a deactivation pathway and not a bioactivation scheme. | |
dc.language.iso | en_US | en_US |
dc.publisher | The University of Arizona. | en_US |
dc.rights | Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. | en_US |
dc.subject | Biology, Molecular. | en_US |
dc.subject | Health Sciences, Pharmacology. | en_US |
dc.subject | Health Sciences, Oncology. | en_US |
dc.title | Mechanistic studies of the cytotoxic action of selected azonafide analogs | en_US |
dc.type | text | en_US |
dc.type | Dissertation-Reproduction (electronic) | en_US |
thesis.degree.grantor | University of Arizona | en_US |
thesis.degree.level | doctoral | en_US |
dc.identifier.proquest | 9814421 | en_US |
thesis.degree.discipline | Graduate College | en_US |
thesis.degree.discipline | Pharmacology & Toxicology | en_US |
thesis.degree.name | Ph.D. | en_US |
dc.description.note | This item was digitized from a paper original and/or a microfilm copy. If you need higher-resolution images for any content in this item, please contact us at repository@u.library.arizona.edu. | |
dc.identifier.bibrecord | .b37743132 | en_US |
dc.description.admin-note | Original file replaced with corrected file October 2023. | |
refterms.dateFOA | 2018-05-29T05:14:04Z | |
html.description.abstract | The cytotoxic mechanism of selected anthracene-containing, DNA-intercalating antitumor agents (azonafides) was investigated. The hypothesis tested was that these compounds kill tumor cells via poisoning DNA topoisomerase II (TOPO II). This hypothesis was based on observations that similar DNA intercalators poison TOPO II as a contributing mechanism to their cytotoxicity. The agents studied had nuclear effects similar to other DNA intercalators. The azonafides inhibited DNA and RNA synthesis with lesser effects on protein synthesis. They produced DNA damage consistent with TOPO II poisoning, including single strand breaks, double strand breaks and DNA/protein crosslinks. Of the five analogs studied, the two with the greatest cytotoxic potency produced less DNA damage than the other analogs. Furthermore, the DNA damage produced by these two highly toxic analogs did not correlate with their cytotoxic potencies whereas the DNA damage production by the less toxic analogs did. This observation suggests that there may be disparate mechanisms of toxicity among the azonafides. All analogs studied inhibited the activity of purified TOPO II. However, there was no evidence of TOPO II poisoning in these experiments. Intracellular TOPO II poisoning assays revealed that only two of the five analogs poisoned TOPO II. This suggests that TOPO II poisoning is involved in the mechanism of action of some azonafide analogs. However, like other DNA intercalators, there may be alternate, possibly novel, mechanisms involved in their toxicity. Additional studies investigated the effect of metabolism on the activity of the parent compound (azonafide). Four metabolites resulting from in vitro metabolism of azonafide were identified including two desmethyl species, an N-oxide metabolite and a carboxylic acid metabolite. The two desmethyl species retained cytotoxic activity and inhibited TOPO II, but were less potent than the parent. The N-oxide and carboxylic acid metabolites were inactive in cytotoxicity analyses. These findings show that metabolism of azonafide represents a deactivation pathway and not a bioactivation scheme. |