Frontiers in Anti-Cancer Drug Discovery

Volume: 3

Innovative Therapeutics Targeting Topoisomerases in Cancer

Author(s): Ahmad Raza, Ryan Etchison, Blake A. Jacobson and Robert A. Kratzke

Pp: 3-31 (29)

DOI: 10.2174/9781608058846114030003

* (Excluding Mailing and Handling)

Abstract

DNA topoisomerases are promising targets in the development of cancer therapeutics. They are comprised of a large number of structurally diverse compounds and function by trapping the DNA-enzyme covalent complex, resulting in DNA strand breaks that can ultimately lead to cancer cell death. Topoisomerases are broadly classified as type I and type II. Type I enzyme (hTopoI) transiently breaks the DNA strands one at a time, while type II enzyme (hTopoII) forms a dimeric enzyme molecule that transiently breaks both DNA strands in the double helix in concert. Camptothecin was first isolated from a tree Camptotheca acuminate, which showed evidence of hTopI poisoning. Irinotecan and topotecan, two camptothecin analogs designed to be soluble, are widely used in clinical practice. Because of the instability of these analogs, however, other hTopoI inhibitors are being introduced that are more potent and stable. Drugs that interfere with hTopoII are typically classified by their mechanism of action. Poisons (including etoposide and doxorubicin) stabilize the covalent TopoII-5´ phosphotyrosyl DNA intermediate or cleavable complex. hTopoII catalytic inhibitors inhibit the enzymatic activity of hTopoII by disrupting the enzymatic recognition of DNA without causing DNA breaks. Recently described hTopoII catalytic inhibitors include aclarubicine, which is successfully used in clinical oncology practice. A series of 9-aminoacridine compounds with hTopoII inhibitor activity have shown promise in inhibiting pancreatic cancer cell proliferation in vivo and have been shown to induce apoptosis. On the basis of the hypothesis that targeting both hTopoI and hTopoII might increase overall anti-tumor activity and overcome resistance, compounds with dual inhibitor activity have been described and are under investigation. In conclusion, the area of topoisomerase inhibitors in cancer therapeutics is evolving and development of dual inhibitors, catalytic inhibitors of hTopoII, and specific inhibitors of hTopoII α isoforms will help to identify more potent compounds with fewer side effects.


Keywords: Apoptosis, cancer, catalytic inhibitors, DNA strand breaks, DNA topoisomerase, hTopoI, hTopoII, topoisomerase poisons.

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      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1518
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59584110 and j.to_ip >=59584110 )) and ((j.from_date <= 1740514902 and j.to_date >= 1740514902 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 6345) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59584110 and j.to_ip >=59584110 )) and ((j.from_date <= 1740514902 and j.to_date >= 1740514902 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 6345) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59584110 and j.to_ip >=59584110 )) and ((j.from_date <= 1740514902 and j.to_date >= 1740514902 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 6345)
      590μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1549
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` where `b`.`banner_ebook` = 1 and `bd`.`content_type` = 'B' and `bd`.`content_id` = 1495 and `b`.`banner_from_date` <= 1740514903 and `b`.`banner_to_date` >= 1740514903 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.09msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: B
      • 2: 1495
      • 3: 1740514903
      • 4: 1740514903
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='01b1b13437ddef92ea8d7573906eb504'
      250μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\Keywords
    8Keywords.php#?
    App\Models\Chapter
    1Chapter.php#?
    App\Models\Ebook
    1Ebook.php#?
        _token
        osA6ZKzEfrw6Zh3OKBNd4a81E3USfRVKS5S8FMWZ
        uc_cart_id
        01b1b13437ddef92ea8d7573906eb504
        _previous
        array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/6345" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/6345
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:17 [ "x-https" => array:1 [ 0 => "1" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] "priority" => array:1 [ 0 => "u=0, i" ] "cookie" => array:1 [ 0 => "wayfindertarget=eyJpdiI6IlZ4WFFHdFZUcThQcDJZcGJYME91Z1E9PSIsInZhbHVlIjoiZVYyaEtwNU95SDNhSTZEcllBSGNwNENNQWZOZSsxcE9VVWdTWGYrMmhERT0iLCJtYWMiOiI3MjFlZjBkN2I3NDllMTdjOGU1YWU2NDk1MjQzOGM1ZTYwNzBhOWZlMDg2OGM4NjdlNzQ4YzdiNGI0ZGQ4YTMwIiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6IlZ4WFFHdFZUcThQcDJZcGJYME91Z1E9PSIsInZhbHVlIjoiZVYyaEtwNU95SDNhSTZEcllBSGNwNENNQWZOZSsxcE9VVWdTWGYrMmhERT0iLCJtYWMiOiI3MjFlZjBkN2I3NDll" ] "accept-encoding" => array:1 [ 0 => "gzip, deflate, br, zstd" ] "sec-fetch-dest" => array:1 [ 0 => "document" ] "sec-fetch-user" => array:1 [ 0 => "?1" ] "sec-fetch-mode" => array:1 [ 0 => "navigate" ] "sec-fetch-site" => array:1 [ 0 => "none" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "sec-ch-ua-platform" => array:1 [ 0 => ""Windows"" ] "sec-ch-ua-mobile" => array:1 [ 0 => "?0" ] "sec-ch-ua" => array:1 [ 0 => ""HeadlessChrome";v="129", "Not=A?Brand";v="8", "Chromium";v="129"" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] ]
        request_cookies
        0 of 0
        array:1 [ "wayfindertarget" => null ]
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Tue, 25 Feb 2025 20:21:43 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6Im9GNVpWbUk2WWZuZFMzTXZ2dk5jY2c9PSIsInZhbHVlIjoiMEMwZEVoSy9MWkkzczArUktOdHg4OTZHeFg5Z25nQ3FqQjJ3d1Q3dUcyVVZVODArcHc4elkwMFNtYWR4M3JNVERqWWI1bW9uMEZ3UmJhSko3NWpxaGh1SG1odU1mVnRCalkrMU4veG9hTUN3S2I0cEpYN3B2enZUbXdtdmwrT0YiLCJtYWMiOiI0YjczYmI3YWQxMzY5M2E0N2JkNjI4N2UzNTg3ZTlhOTJjMTc5MzgxOTViNGM1ZDQzZTlhOWEwN2E2YzVlODZmIiwidGFnIjoiIn0%3D; expires=Fri, 28 Feb 2025 08:21:43 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6Im9GNVpWbUk2WWZuZFMzTXZ2dk5jY2c9PSIsInZhbHVlIjoiMEMwZEVoSy9MWkkzczArUktOdHg4OTZHeFg5Z25nQ3FqQjJ3d1Q3dUcyVVZVODArcHc4elkwMFNtYWR4M3JNVERqWWI1b" 1 => "alphaeurekaselectnet_session=eyJpdiI6Ik1OTGp3NmhlSlBxRG5zcHF6SVovc2c9PSIsInZhbHVlIjoiNURaaHlnWWZsWUdGM0U4OVZqd0FkczJOMXVudnZkdExUd2szdmNUTU5VQUdmTk1LR0xibFRlTXZMa1VTZFVGSG1HUkd1RzZySHVENU5GVGJpY3p3OWJnTWpleS9KYmp5UW5kUWROYW9BazhLbXB6cWVESG1ua1BXQ2FHbjN0MkYiLCJtYWMiOiI2MDdhY2UxZTA2N2YyMjVjYmQ2MzZlMjA1YTZiZTRjODBmZjBkMmYwY2ZmZmI5NjU3NTk5NTA1MDBkNjhmODkyIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6Ik1OTGp3NmhlSlBxRG5zcHF6SVovc2c9PSIsInZhbHVlIjoiNURaaHlnWWZsWUdGM0U4OVZqd0FkczJOMXVudnZkdExUd2szdmNUTU5VQUdmTk1LR0xibFRlTXZ" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6Im9GNVpWbUk2WWZuZFMzTXZ2dk5jY2c9PSIsInZhbHVlIjoiMEMwZEVoSy9MWkkzczArUktOdHg4OTZHeFg5Z25nQ3FqQjJ3d1Q3dUcyVVZVODArcHc4elkwMFNtYWR4M3JNVERqWWI1bW9uMEZ3UmJhSko3NWpxaGh1SG1odU1mVnRCalkrMU4veG9hTUN3S2I0cEpYN3B2enZUbXdtdmwrT0YiLCJtYWMiOiI0YjczYmI3YWQxMzY5M2E0N2JkNjI4N2UzNTg3ZTlhOTJjMTc5MzgxOTViNGM1ZDQzZTlhOWEwN2E2YzVlODZmIiwidGFnIjoiIn0%3D; expires=Fri, 28-Feb-2025 08:21:43 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6Im9GNVpWbUk2WWZuZFMzTXZ2dk5jY2c9PSIsInZhbHVlIjoiMEMwZEVoSy9MWkkzczArUktOdHg4OTZHeFg5Z25nQ3FqQjJ3d1Q3dUcyVVZVODArcHc4elkwMFNtYWR4M3JNVERqWWI1b" 1 => "alphaeurekaselectnet_session=eyJpdiI6Ik1OTGp3NmhlSlBxRG5zcHF6SVovc2c9PSIsInZhbHVlIjoiNURaaHlnWWZsWUdGM0U4OVZqd0FkczJOMXVudnZkdExUd2szdmNUTU5VQUdmTk1LR0xibFRlTXZMa1VTZFVGSG1HUkd1RzZySHVENU5GVGJpY3p3OWJnTWpleS9KYmp5UW5kUWROYW9BazhLbXB6cWVESG1ua1BXQ2FHbjN0MkYiLCJtYWMiOiI2MDdhY2UxZTA2N2YyMjVjYmQ2MzZlMjA1YTZiZTRjODBmZjBkMmYwY2ZmZmI5NjU3NTk5NTA1MDBkNjhmODkyIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6Ik1OTGp3NmhlSlBxRG5zcHF6SVovc2c9PSIsInZhbHVlIjoiNURaaHlnWWZsWUdGM0U4OVZqd0FkczJOMXVudnZkdExUd2szdmNUTU5VQUdmTk1LR0xibFRlTXZ" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "osA6ZKzEfrw6Zh3OKBNd4a81E3USfRVKS5S8FMWZ" "uc_cart_id" => "01b1b13437ddef92ea8d7573906eb504" "_previous" => array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/6345" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-25 20:21:43GET/chapter/63451121910