Structure-function dependence and allopurinol inhibition of radiosensitizer/nitroreductase interaction: approaches to improving therapeutic ratios
Normal tissue toxicity of nitroaromatic radiosensitizers may originate in radiosensitizer/nitroreductase interaction. A study of two mammalian cell nitroreductases, xanthine oxidase and NADH cytochrome c reductase, shows that the efficiency of electron transfer is dependent on sensitizer electron af...
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| Veröffentlicht in: | Cancer clinical trials 1980, Vol.3 (1), p.55 |
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| creator | Raleigh, J A Shum, F Y Koziol, D R Saunders, W M |
| description | Normal tissue toxicity of nitroaromatic radiosensitizers may originate in radiosensitizer/nitroreductase interaction. A study of two mammalian cell nitroreductases, xanthine oxidase and NADH cytochrome c reductase, shows that the efficiency of electron transfer is dependent on sensitizer electron affinity and not lipid solubility. Misonidazole and its demethylated metabolite (RO-05-9963), for example, are equally efficient as electron acceptors from xanthine oxidase. The only exception to the electron affinity correlation is m-nitrobenzamidine hydrochloride (MNBAM) which results because MNBAM inhibits electron donation to xanthine oxidase from its cofactor, xanthine. Allopurinol inhibits electron transfer and might be a useful adjuvant to the use of radiosensitizers. Evidence that allopurinol interacts with nitroreductases in vivo is deduced from the observation that allopurinol significantly alters the serum lifetimes in mice of misonidazole and RO-05-9963. |
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A study of two mammalian cell nitroreductases, xanthine oxidase and NADH cytochrome c reductase, shows that the efficiency of electron transfer is dependent on sensitizer electron affinity and not lipid solubility. Misonidazole and its demethylated metabolite (RO-05-9963), for example, are equally efficient as electron acceptors from xanthine oxidase. The only exception to the electron affinity correlation is m-nitrobenzamidine hydrochloride (MNBAM) which results because MNBAM inhibits electron donation to xanthine oxidase from its cofactor, xanthine. Allopurinol inhibits electron transfer and might be a useful adjuvant to the use of radiosensitizers. Evidence that allopurinol interacts with nitroreductases in vivo is deduced from the observation that allopurinol significantly alters the serum lifetimes in mice of misonidazole and RO-05-9963.</description><identifier>ISSN: 0190-1206</identifier><identifier>PMID: 6771029</identifier><language>eng</language><publisher>United States</publisher><subject>Allopurinol - pharmacology ; Animals ; Benzamidines - metabolism ; Cells, Cultured ; Cricetinae ; Cricetulus ; Dose-Response Relationship, Drug ; Female ; Furylfuramide - pharmacology ; Hydrogen-Ion Concentration ; Mice ; Mice, Inbred BALB C ; Misonidazole - analogs & derivatives ; Misonidazole - blood ; Misonidazole - metabolism ; NADPH-Ferrihemoprotein Reductase - metabolism ; Radiation-Sensitizing Agents - antagonists & inhibitors ; Structure-Activity Relationship ; Temperature ; Xanthine Oxidase - metabolism</subject><ispartof>Cancer clinical trials, 1980, Vol.3 (1), p.55</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/6771029$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Raleigh, J A</creatorcontrib><creatorcontrib>Shum, F Y</creatorcontrib><creatorcontrib>Koziol, D R</creatorcontrib><creatorcontrib>Saunders, W M</creatorcontrib><title>Structure-function dependence and allopurinol inhibition of radiosensitizer/nitroreductase interaction: approaches to improving therapeutic ratios</title><title>Cancer clinical trials</title><addtitle>Cancer Clin Trials</addtitle><description>Normal tissue toxicity of nitroaromatic radiosensitizers may originate in radiosensitizer/nitroreductase interaction. A study of two mammalian cell nitroreductases, xanthine oxidase and NADH cytochrome c reductase, shows that the efficiency of electron transfer is dependent on sensitizer electron affinity and not lipid solubility. Misonidazole and its demethylated metabolite (RO-05-9963), for example, are equally efficient as electron acceptors from xanthine oxidase. The only exception to the electron affinity correlation is m-nitrobenzamidine hydrochloride (MNBAM) which results because MNBAM inhibits electron donation to xanthine oxidase from its cofactor, xanthine. Allopurinol inhibits electron transfer and might be a useful adjuvant to the use of radiosensitizers. Evidence that allopurinol interacts with nitroreductases in vivo is deduced from the observation that allopurinol significantly alters the serum lifetimes in mice of misonidazole and RO-05-9963.</description><subject>Allopurinol - pharmacology</subject><subject>Animals</subject><subject>Benzamidines - metabolism</subject><subject>Cells, Cultured</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Dose-Response Relationship, Drug</subject><subject>Female</subject><subject>Furylfuramide - pharmacology</subject><subject>Hydrogen-Ion Concentration</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Misonidazole - analogs & derivatives</subject><subject>Misonidazole - blood</subject><subject>Misonidazole - metabolism</subject><subject>NADPH-Ferrihemoprotein Reductase - metabolism</subject><subject>Radiation-Sensitizing Agents - antagonists & inhibitors</subject><subject>Structure-Activity Relationship</subject><subject>Temperature</subject><subject>Xanthine Oxidase - metabolism</subject><issn>0190-1206</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1980</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNotkM1KAzEUhbNQaq0-gpAXGMxM5tedFP-g4EJdl5vkxonMJCHJCPoYPrGh7epyDh8fnHtG1qwcWFFWrL0glzF-McZ5V_crsmq7rmTVsCZ_byksMi0BC71YmYyzVKFHq9BKpGAVhWlyfgnGuokaOxphDpTTNIAyLqKNufnFcGtNCi6gykKImOGEAQ7OOwreBwdyxEiTo2bO6dvYT5rGzHhckpHZl9l4Rc41TBGvT3dDPh4f3rfPxe716WV7vyt8HpQK5LpH1qqyBVZrlEPDa6GGsum1BmhqrEA1shcSRSOU4B3ogdU9F5o1om1rviE3R69fxIxq74OZIfzsT7_h_6eqZmk</recordid><startdate>1980</startdate><enddate>1980</enddate><creator>Raleigh, J A</creator><creator>Shum, F Y</creator><creator>Koziol, D R</creator><creator>Saunders, W M</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>1980</creationdate><title>Structure-function dependence and allopurinol inhibition of radiosensitizer/nitroreductase interaction: approaches to improving therapeutic ratios</title><author>Raleigh, J A ; Shum, F Y ; Koziol, D R ; Saunders, W M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p206t-e3f8e06d16a04fec9534bd9158ffaa54e2ad5c8bceb5bdb37af90483bf05b6643</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1980</creationdate><topic>Allopurinol - pharmacology</topic><topic>Animals</topic><topic>Benzamidines - metabolism</topic><topic>Cells, Cultured</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Dose-Response Relationship, Drug</topic><topic>Female</topic><topic>Furylfuramide - pharmacology</topic><topic>Hydrogen-Ion Concentration</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Misonidazole - analogs & derivatives</topic><topic>Misonidazole - blood</topic><topic>Misonidazole - metabolism</topic><topic>NADPH-Ferrihemoprotein Reductase - metabolism</topic><topic>Radiation-Sensitizing Agents - antagonists & inhibitors</topic><topic>Structure-Activity Relationship</topic><topic>Temperature</topic><topic>Xanthine Oxidase - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Raleigh, J A</creatorcontrib><creatorcontrib>Shum, F Y</creatorcontrib><creatorcontrib>Koziol, D R</creatorcontrib><creatorcontrib>Saunders, W M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Cancer clinical trials</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Raleigh, J A</au><au>Shum, F Y</au><au>Koziol, D R</au><au>Saunders, W M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure-function dependence and allopurinol inhibition of radiosensitizer/nitroreductase interaction: approaches to improving therapeutic ratios</atitle><jtitle>Cancer clinical trials</jtitle><addtitle>Cancer Clin Trials</addtitle><date>1980</date><risdate>1980</risdate><volume>3</volume><issue>1</issue><spage>55</spage><pages>55-</pages><issn>0190-1206</issn><abstract>Normal tissue toxicity of nitroaromatic radiosensitizers may originate in radiosensitizer/nitroreductase interaction. A study of two mammalian cell nitroreductases, xanthine oxidase and NADH cytochrome c reductase, shows that the efficiency of electron transfer is dependent on sensitizer electron affinity and not lipid solubility. Misonidazole and its demethylated metabolite (RO-05-9963), for example, are equally efficient as electron acceptors from xanthine oxidase. The only exception to the electron affinity correlation is m-nitrobenzamidine hydrochloride (MNBAM) which results because MNBAM inhibits electron donation to xanthine oxidase from its cofactor, xanthine. Allopurinol inhibits electron transfer and might be a useful adjuvant to the use of radiosensitizers. Evidence that allopurinol interacts with nitroreductases in vivo is deduced from the observation that allopurinol significantly alters the serum lifetimes in mice of misonidazole and RO-05-9963.</abstract><cop>United States</cop><pmid>6771029</pmid></addata></record> |
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| identifier | ISSN: 0190-1206 |
| ispartof | Cancer clinical trials, 1980, Vol.3 (1), p.55 |
| issn | 0190-1206 |
| language | eng |
| recordid | cdi_pubmed_primary_6771029 |
| source | MEDLINE; Journals@Ovid Complete |
| subjects | Allopurinol - pharmacology Animals Benzamidines - metabolism Cells, Cultured Cricetinae Cricetulus Dose-Response Relationship, Drug Female Furylfuramide - pharmacology Hydrogen-Ion Concentration Mice Mice, Inbred BALB C Misonidazole - analogs & derivatives Misonidazole - blood Misonidazole - metabolism NADPH-Ferrihemoprotein Reductase - metabolism Radiation-Sensitizing Agents - antagonists & inhibitors Structure-Activity Relationship Temperature Xanthine Oxidase - metabolism |
| title | Structure-function dependence and allopurinol inhibition of radiosensitizer/nitroreductase interaction: approaches to improving therapeutic ratios |
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