[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-382155-105":59,"doc-detail-382155-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","selective-protection-of-normal-cells-from-chemotherapy-while-killing-drug-resistant-cancer-cells","Selective protection of normal cells from chemotherapy, while killing drug-resistant cancer cells","","Cancer therapy is constrained by toxicity toward normal cells and by drug resistance within cancer cells. A counterintuitive strategy exploits this resistance to protect healthy tissue while enabling selective eradication of resistant cancer clones using antagonistic drug combinations that pair cytotoxic agents with protective drugs. Mechanistic routes include targeting CDK4/6, caspases, Mdm2, mTOR, and mitogenic kinases, with further gains from synergistic add-on drugs to improve selectivity and potency. The review discusses clinical translation of Trilaciclib, management of systemic side effects, and ensuring protective drugs shield normal cells rather than cancer cells.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/selective-protection-of-normal-cells-from-chemotherapy-while-killing-drug-resistant-cancer-cells/382155/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/selective-protection-of-normal-cells-from-chemotherapy-while-killing-drug-resistant-cancer-cells/382155.png","ImageObject",300,407,{"name":92,"@type":93},"Jiven","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why does chemotherapy fail despite targeting cancer cells?","Question",{"text":112,"@type":113},"Chemotherapy can damage normal cells in the organism, which limits tolerable dosing. In parallel, cancer cells inevitably develop both innate and acquired drug resistance, leading to therapy failure.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How can normal cells be protected while resistant cancer cells are killed?",{"text":117,"@type":113},"The approach uses antagonistic drug combinations: a protective component prevents death in normal (sensitive) cells, while a cytotoxic component selectively eliminates resistant clones. The review emphasizes that selectivity depends on the specific resistance mechanisms and drug sensitivities.",{"name":119,"@type":110,"acceptedAnswer":120},"What is the role of Trilaciclib in clinical translation?",{"text":121,"@type":113},"The review describes Trilaciclib as a CDK4/6 inhibitor introduced for myeloprotection against chemotherapy in lung cancer. This clinical success supports translating the broader concept of selective normal-cell protection by exploiting cancer-cell drug resistance.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},382155,1790642658,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},1099513958607,"https://ap-avatar.wpscdn.com/avatar/100002390cf8733938c?x-image-process=image/resize,m_fixed,w_180,h_180&k=1778829742770036399","[www.oncotarget.com](www.oncotarget.com) Oncotarget, 2023, Vol. 14, pp: 193-206  \nReview  \nSelective protection of normal cells from chemotherapy, while killing drug-resistant cancer cells  \nMikhail V . Blagosklonny 1  \n1 Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA  \nCorrespondence to: Mikhail V. Blagosklonny, [email](email: Blagosklonny@oncotarget.com)[: Blagosklonny@oncotarget.com](email: Blagosklonny@oncotarget.com), [Blagosklonny@rapalogs.com](Blagosklonny@rapalogs.com)[ ](Blagosklonny@rapalogs.com)Keywords: oncology; resistance; cyclotherapy; trilaciclib; rapamycin  \nReceived: January 05, 2023 Accepted: March 01, 2023 Published: March 11, 2023  \nCopyright: © 2023 Blagosklonny. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.  \nABSTRACT  \nCancer therapy is limited by toxicity in normal cells and drug-resistance in cancer cells. Paradoxically, cancer resistance to certain therapies can be exploited for protection of normal cells, simultaneously enabling the selective killing of resistant cancer cells by using antagonistic drug combinations, which include cytotoxic and protective drugs. Depending on the mechanisms of drug-resistance in cancer cells, the protection of normal cells can be achieved with inhibitors of CDK4/6, caspases, Mdm2, mTOR, and mitogenic kinases. When normal cells are protected, the selectivity and potency of multi-drug combinations can be further enhanced by adding synergistic drugs, in theory, eliminating the deadliest cancer clones with minimal side effects. I also discuss how the recent success of Trilaciclib may foster similar approaches into clinical practice, how to mitigate systemic side effects of chemotherapy in patients with brain tumors and how to ensure that protective drugs would only protect normal cells (not cancer cells) in a particular patient.  \nINTRODUCTION  \nNo cancer cell, no matter how resistant it is, can survive chemotherapy in a cell culture. In the organism, however, therapy of cancer is limited by killing or damaging normal cells. Selective protection of normal cells from chemotherapy would increase the therapeutic window, improving the therapeutic outcome. Needless to say, reduction of side effects and better quality of life are very important for a cancer patient.  \nThe challenge is to ensure that protection of normal cells is selective or, in other words, that cancer cells are not protected. Here, we will discuss approaches to ensure selectivity. We will also discuss how multi-drug combinations could be designed to be antagonistic in normal cells and synergistic in cancer cells. Pre-clinical studies in paired cell lines and mice demonstrated that normal cells can be selectively protected. However, until recently, there was little hope of clinical application because this research was little known and seemed impracticable and obscure. The situation is radically changing now because, based in part on the outstanding work of Norman Sharpless and co-workers [1, 2], the  \nCDK4/6 inhibitor Trilaciclib was successfully introduced for myeloprotection against chemotherapy in lung cancer. This success creates the opportunity for clinical translation of the entire concept: selective protection of normal cells by exploiting drug resistance of cancer cells.  \nTo start with, some cancers are intrinsically resistant to anticancer drugs [3, 4] . Furthermore, apoptosis avoidance, mitogenic self-sufficiency and insensitivity to anti-proliferative stimuli are hallmarks of cancer [5] . Killing sensitive cancer cells, an initially effective cancer therapy, inevitably selects for acquired resistance. Resistant clones tend to be aggressive due to acquiring additional oncogenic mutations. This is how therapy fails.  \nIn 1999, it was suggested to exploit resistance instead of its rev","cbCainUftHTcEfKH","https://ap.wps.com/l/cbCainUftHTcEfKH","pdf",1671340,14,"English","# Abstract\n# Introduction\n## Selective protection concept\n## Drug resistance as exploitable mechanism\n## Designing antagonistic multi-drug combinations\n# Solving the puzzle\n## Paired cell-line strategy and dosing logic\n## Low-DOX and PTX for selective killing\n# Figure 1 overview","[{\"question\":\"Why does chemotherapy fail despite targeting cancer cells?\",\"answer\":\"Chemotherapy can damage normal cells in the organism, which limits tolerable dosing. In parallel, cancer cells inevitably develop both innate and acquired drug resistance, leading to therapy failure.\"},{\"question\":\"How can normal cells be protected while resistant cancer cells are killed?\",\"answer\":\"The approach uses antagonistic drug combinations: a protective component prevents death in normal (sensitive) cells, while a cytotoxic component selectively eliminates resistant clones. The review emphasizes that selectivity depends on the specific resistance mechanisms and drug sensitivities.\"},{\"question\":\"What is the role of Trilaciclib in clinical translation?\",\"answer\":\"The review describes Trilaciclib as a CDK4/6 inhibitor introduced for myeloprotection against chemotherapy in lung cancer. This clinical success supports translating the broader concept of selective normal-cell protection by exploiting cancer-cell drug resistance.\"}]","Selective protection of normal cells from chemotherapy, while killing drug-resistant cancer cells | PDF",1790249307,35]