Ebook Designing multi-target drugs: Part 2
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Ebook Designing multi-target drugs: Part 2
CHAPTER 11Combination Agents Versus Multi-Targeted Agents -Pros and ConsJOSE G. MONZON AND JANET DANCEY*National Cancer Institute of Canada, Clinical Ebook Designing multi-target drugs: Part 2 Trials Group, 10 Stuart Street, Kingston, ON K7L 3N6. Canada*Emai 1: jdancey@ctg.queensu.ca11.1IntroductionAlthough the vast majority of diseases are multi-factorial in nature, most modern drug discovery is based on identifying a drug that acts on a single derangement felt to be involved in disease Ebook Designing multi-target drugs: Part 2 development or progression. Due to the multi-factorial nature of most diseases, a selective compound for a single target rarely achieves the desiredEbook Designing multi-target drugs: Part 2
effect and is often combined with standard treatments or other novel targeted agents to improve effectiveness. This could not be truer for novel anti-CHAPTER 11Combination Agents Versus Multi-Targeted Agents -Pros and ConsJOSE G. MONZON AND JANET DANCEY*National Cancer Institute of Canada, Clinical Ebook Designing multi-target drugs: Part 2of combinations is likely due to the fact that cancer is a heterogeneous disease among patients and within the same patient. Cancer cells are genotypically and phcnotypically complex and adaptive. There may be de novo protective mechanisms that render individual drugs ineffective. In addition, acqui Ebook Designing multi-target drugs: Part 2red resistance occurs with almost all agents over time unless the therapy is curative. Historically, the goal of cytotoxic agents was to maximizeRSC DEbook Designing multi-target drugs: Part 2
rug Discovery Series No. 21Designing Multi-Targel DrugsEdited by J. Richard Morphy and c. John Harris(t Royal Society of Chemistry 2012Published by thCHAPTER 11Combination Agents Versus Multi-Targeted Agents -Pros and ConsJOSE G. MONZON AND JANET DANCEY*National Cancer Institute of Canada, Clinical Ebook Designing multi-target drugs: Part 2 their disruption of the frequent cell division and DNA replication of cancer cells relative to most normal cells. Most cytotoxic cancer drugs act by inhibiting synthesis of DNA precursors, damaging the DNA template, or disrupting chromosomal segregation. However, rapidly dividing normal tissues, su Ebook Designing multi-target drugs: Part 2ch as those of the bone marrow, gastrointestinal tract, and hair follicles were also affected. Ultimately, these side effects would result in suboplimEbook Designing multi-target drugs: Part 2
al dosing because of normal tissue toxicity, resulting in reduced efficacy. drug resistance, and decreased quality of life for patients. In contrast, CHAPTER 11Combination Agents Versus Multi-Targeted Agents -Pros and ConsJOSE G. MONZON AND JANET DANCEY*National Cancer Institute of Canada, Clinical Ebook Designing multi-target drugs: Part 2ckade of cancerrelevant targets in properly selected patients.Following decades of research, a plethora of genes have been identified that arc differentially expressed in cancer cells with the potential to act as molecular targets for anti-cancer drugs. Numerous molecularly targeted agents are now a Ebook Designing multi-target drugs: Part 2pproved (see Table 11.1) and are being developed, with the hopes that they have improved anti-cancer activity and fewer side effects. One of the mainEbook Designing multi-target drugs: Part 2
differences between the development of conventional cytotoxic agents and newer targeted agents is in the way they are designed. Cytotoxic agents were CHAPTER 11Combination Agents Versus Multi-Targeted Agents -Pros and ConsJOSE G. MONZON AND JANET DANCEY*National Cancer Institute of Canada, Clinical Ebook Designing multi-target drugs: Part 2apidly proliferating human or murine cancer cell lines. Now, a more rational approach to drugTable 11.1 Approved molecularly targeted agents.AgentTargetTuntour typeAgent classImalinibBCR-ABL chromosomal translocation, PDGFR. C-KITCML, CM ML, ALL, DFSP, GISTTKIDasatinibBCR-ABL chromosomal translocati Ebook Designing multi-target drugs: Part 2onCML. ALLTKIErlotinibEGERNSCLCTKICetuximabEGFRCRC. Head and NeckMonoclonal antibodyPanitmumabEGFRCRCMonoclonal antibodyTrastuzumabHER2BreastMonoclonaEbook Designing multi-target drugs: Part 2
l antibodyLapalinibHER2BreastTKIBevacizumabVEGFCRC. NSCLCMonoclonal antibodySunitinibVEGFRKidneyTKISorafenibVEGFRKidneyTKITcmsirolimusmTORKidneyRapamyCHAPTER 11Combination Agents Versus Multi-Targeted Agents -Pros and ConsJOSE G. MONZON AND JANET DANCEY*National Cancer Institute of Canada, Clinical Ebook Designing multi-target drugs: Part 2CLHydroxamic acidBortczcmibProtcosomcMultiple MyelomaProteosome inhibitorAbbreviations: ALL, acute lymphocytic leukemia; BCR-A BL, break-point cluster region-Abelson; CM I., chronic myelogenous leukemia; CM ML, chronic myelomonocytic leukemia; CRC, colorectal cancer; CTCL, cutaneous. T-cell leukemia Ebook Designing multi-target drugs: Part 2: DFSP, dermatofibrosarcoma protubcrans; EGFR, epidermal growth factor receptor; HER2. human epidermal growth factor receptor 2; MDS. myelodysplasticEbook Designing multi-target drugs: Part 2
syndrome; rn'I'OR, mammalian target ol'rapamycin; NSCLC, non-small cell lung cancer; TK1. tyrosine kinase inhibitor, VEGF, vascular endothelial growthCHAPTER 11Combination Agents Versus Multi-Targeted Agents -Pros and ConsJOSE G. MONZON AND JANET DANCEY*National Cancer Institute of Canada, Clinical CHAPTER 11Combination Agents Versus Multi-Targeted Agents -Pros and ConsJOSE G. MONZON AND JANET DANCEY*National Cancer Institute of Canada, ClinicalGọi ngay
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