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-'''ANS: ''' The molecules of receptors show structural and functional changes, and it may have particular drug affinities (particular pharmacodynamic responses) in various states. This mechanism is easily incorporated by a two-state model.<ref name=":0">{{Cite web |last=Yartsev |first=Alex |title=Receptor theory of drug action {{!}} Deranged Physiology |url=https://derangedphysiology.com/main/cicm-primary-exam/pharmacodynamics/Chapter-118/receptor-theory-drug-action#:~:text=The%20Two%20State%20Model%20permits%20the%20possibility%20of%20%22baseline%20activity%22%20(i.e.%20receptor,therefore%20allows |access-date=2024-10-11 |website=derangedphysiology.com |language=en}}</ref> The two-state receptor model describes the interaction between a ligand and its receptor as a system where the receptor exists in two states: an inactive state (R) and an active state (R*).<ref name=":1">{{Citation |title=Receptor theory |date=2023-06-04 |work=Wikipedia |url=https://en.wikipedia.org/wiki/Receptor_theory#:~:text=Two-state,receptor%20theory |access-date=2024-10-11 |language=en}}</ref> It was first used by Katz and Thesleff (1957) to explain suxamethonium's impact on acetylcholine-gated ion channels at the motor endplate.<ref name=":0" />
-The allosteric constant (L), which is the ratio of active to inactive receptors, was also introduced by this model. This model allows for a baseline level of receptor activation, i.e. receptor activity in the absence of agonist medication. This notion gives birth to the possibility of inverse agonists, which are medicines that impact L by reducing baseline receptor activity.<ref name=":0" />
-However, several issues surround the use of this model:
-Simplification of Receptor activity: Because the two-state model assumes only two states, it may not correctly describe the complicated activity of numerous receptors that can exist in multiple conformations.<ref name=":1" /><ref>{{Cite journal |last=Rang |first=H P |date=2006-01 |title=The receptor concept: pharmacology's big idea |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1760743/#:~:text=Not%20surprisingly,%20the%20simple%20two-state%20model%20could%20not%20explain%20everything%20about,mechanisms%20were |journal=British Journal of Pharmacology |volume=147 |issue=Suppl 1 |pages=S9–S16 |doi=10.1038/sj.bjp.0706457 |issn=0007-1188 |pmc=1760743 |pmid=16402126}}</ref>
-Inability to Explain Certain Drug Actions: Certain medications, such as dobutamine, provide difficulties since their mechanisms of action do not fit cleanly into the two-state paradigm. This shows that the model may not fully represent all receptor-ligand interactions.<ref name=":1" />
-Predictive Limitations: The model struggles to anticipate receptor activation results in increasingly complicated systems, especially those with sophisticated signaling networks.<ref name=":0" />
-Need for Alternative Models: By adding new components like G-proteins and considering the effects of allosteric modulators, alternative models—such the ternary complex model—have been put forth to offer a more thorough understanding of receptor interactions. <ref name=":1" />
-In general, although the two-state receptor model has established a foundation for comprehending pharmacological interactions, acknowledging its constraints is essential for the progression of receptor theory.
-.     (50 pts) Describe why the extracellular matrix makes a good target for drug development.
-'''ANS:''' Extracellular matrix (ECM) is a useful target for drug development since it possesses a number of unique properties, especially when it comes to cancer and other disorders.
-               i.         Multifunctionality:
-In addition to supporting tissues structurally, the extracellular matrix (ECM) helps in cell migration, proliferation, and signaling. The extracellular matrix (ECM) has the ability to modify cellular behavior via affecting several biological processes, particularly in the tumor microenvironment.<ref name=":2">{{Cite journal |last=Hwang |first=Jeongmin |last2=Sullivan |first2=Millicent O. |last3=Kiick |first3=Kristi L. |date=2020-02-18 |title=Targeted Drug Delivery via the Use of ECM-Mimetic Materials |url=https://www.frontiersin.org/journals/bioengineering-and-biotechnology/articles/10.3389/fbioe.2020.00069/full |journal=Frontiers in Bioengineering and Biotechnology |language=English |volume=8 |doi=10.3389/fbioe.2020.00069 |issn=2296-4185}}</ref>
-§  Interaction of Tumor Microenvironment:
-When it comes to cancer, the extracellular matrix (ECM) plays a major role in the tumor microenvironment (TME), which affects the growth and evolution of the tumor.<ref>{{Cite journal |last=Huang |first=Jiacheng |last2=Zhang |first2=Lele |last3=Wan |first3=Dalong |last4=Zhou |first4=Lin |last5=Zheng |first5=Shusen |last6=Lin |first6=Shengzhang |last7=Qiao |first7=Yiting |date=2021-04-23 |title=Extracellular matrix and its therapeutic potential for cancer treatment |url=https://www.nature.com/articles/s41392-021-00544-0 |journal=Signal Transduction and Targeted Therapy |language=en |volume=6 |issue=1 |pages=1–24 |doi=10.1038/s41392-021-00544-0 |issn=2059-3635}}</ref> It is possible to interfere with the supporting environment that promotes drug resistance and cancer cell survival by targeting the ECM remodeling that occurs during carcinogenesis.
-             ii.         Structure and Composition:
-The extracellular matrix (ECM) is made up of many proteins, including glycoproteins and collagens, elastin, and laminins, that combine to form a complex network that can alter in response to pathological circumstances. ECM’s dynamic nature makes it possible to identify particular components that can be the subject of pharmacological targeting.<ref>{{Cite journal |last=Huxley-Jones |first=Julie |last2=Foord |first2=Steven M. |last3=Barnes |first3=Michael R. |date=2008-08-01 |title=Drug discovery in the extracellular matrix |url=https://www.sciencedirect.com/science/article/abs/pii/S1359644608001657#:~:text=The%20extracellular%20matrix%20(ECM)%20is%20a%20complex%20structured%20network%20of%20secreted%20macromolecules%20and,the%20structure |journal=Drug Discovery Today |volume=13 |issue=15 |pages=685–694 |doi=10.1016/j.drudis.2008.05.005 |issn=1359-6446}}</ref><ref name=":3">{{Cite journal |last=Järveläinen |first=Hannu |last2=Sainio |first2=Annele |last3=Koulu |first3=Markku |last4=Wight |first4=Thomas N. |last5=Penttinen |first5=Risto |date=2009-06 |title=Extracellular Matrix Molecules: Potential Targets in
-                Pharmacotherapy |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2830117/#:~:text=The%20extracellular%20matrix%20(ECM)%20is%20composed%20of%20collagens,%20elastin,%20proteoglycans,a%20complex, |journal=Pharmacological Reviews |volume=61 |issue=2 |pages=198–223 |doi=10.1124/pr.109.001289 |issn=0031-6997 |pmc=2830117 |pmid=19549927}}</ref>
-'''§  Biomaterial Innovations:'''
-Innovative biomaterials based on ECM proteins are being developed to boost tissue regeneration and drug delivery capabilities. These materials are designed to actively interact with cells via specialized receptor contacts, enabling real-time reactions to the therapeutic environment.<ref>{{Cite journal |last=Kyriakopoulou |first=Konstantina |last2=Piperigkou |first2=Zoi |last3=Tzaferi |first3=Kyriaki |last4=Karamanos |first4=Nikos K. |date=2023 |title=Trends in extracellular matrix biology |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9884264/#:~:text=Targeting%20of%20ECM%20molecules%20is%20a%20very%20important%20approach%20for%20therapeutic,developing%20four |journal=Molecular Biology Reports |volume=50 |issue=1 |pages=853–863 |doi=10.1007/s11033-022-07931-y |issn=0301-4851 |pmc=9884264 |pmid=36342580}}</ref><ref>{{Cite journal |last=Chen |first=Zhuolin |last2=Du |first2=Chengcheng |last3=Liu |first3=Senrui |last4=Liu |first4=Jiacheng |last5=Yang |first5=Yaji |last6=Dong |first6=Lili |last7=Zhao |first7=Weikang |last8=Huang |first8=Wei |last9=Lei |first9=Yiting |date=2024-08-01 |title=Progress in biomaterials inspired by the extracellular matrix |url=https://www.sciencedirect.com/science/article/pii/S2666542524000870#:~:text=Biomaterials%20inspired%20by%20the%20extracellular%20matrix%20(ECM)%20offer%20unique,cellular%20investigations. |journal=Giant |volume=19 |pages=100323 |doi=10.1016/j.giant.2024.100323 |issn=2666-5425}}</ref>
-           iii.         Barriers to drug delivery:
-Chemotherapy efficacy is often reduced in solid tumors due to drug diffusion being limited by the rigid structure of extracellular matrix (ECM). Drug delivery and therapeutic results have been demonstrated to be improved by strategies targeted at altering the composition of extracellular matrix (ECM) or breaking down its barriers.<ref name=":2" />
-           iv.         Role in Drug Resistance:
-Therapy resistance is linked to changes in the ECM. A change in the extracellular matrix's (ECM) rigidity caused by higher collagen deposition can trigger signaling pathways that support the survival of cancer cells and their resistance to therapeutic interventions.<ref>{{Cite journal |last=Jiang |first=Yangfu |last2=Zhang |first2=Hongying |last3=Wang |first3=Jiao |last4=Liu |first4=Yongliang |last5=Luo |first5=Ting |last6=Hua |first6=Hui |date=2022-03-24 |title=Targeting extracellular matrix stiffness and mechanotransducers to improve cancer therapy |url=https://jhoonline.biomedcentral.com/articles/10.1186/s13045-022-01252-0#:~:text=This%20review%20summarizes%20recent%20work%20on%20the%20regulation%20of%20ECM%20stiffness%20in%20cancer,,and%20drug |journal=Journal of Hematology & Oncology |volume=15 |issue=1 |pages=34 |doi=10.1186/s13045-022-01252-0 |issn=1756-8722}}</ref> By focusing on these changes, therapeutic efficacy may be increased, and resistance may be overcome.
-§  '''Enzyme-Based ECM Disruption:'''
-Strategies for degrading ECM components such as hyaluronic acid using enzymes such as hyaluronidase are being investigated. This method intends to promote medication penetration in solid tumors by temporarily reducing ECM density, therefore boosting the efficacy of chemotherapies.<ref>{{Cite journal |last=Zhao |first=Jingru |last2=Chen |first2=Jing |last3=Li |first3=Changqing |last4=Xiang |first4=Hong |last5=Miao |first5=Xiaoqing |date=2024-10-01 |title=Hyaluronidase overcomes the extracellular matrix barrier to enhance local drug delivery |url=https://www.sciencedirect.com/science/article/abs/pii/S093964112400300X |journal=European Journal of Pharmaceutics and Biopharmaceutics |volume=203 |pages=114474 |doi=10.1016/j.ejpb.2024.114474 |issn=0939-6411}}</ref>
-             v.         Potential for Biomarkers:
-A few elements of ECM can function as biomarkers for prognosis, diagnosis, and treatment response. Different ECM protein levels may be correlated with different tumor kinds, stages, and treatment responses, thereby laying the groundwork for customized therapeutic strategies.
-           vi.         Interaction with Cell Receptors:
-ECM molecules interact with integrins and other cell surface receptors to mediate signaling pathways critical to cell migration and survival. Because of this characteristic, tailored treatments that control these interactions to improve medication efficacy can be created.<ref name=":3" />
-§  '''Targeted Delivery Systems'''
-Drug delivery methods have been designed to use ECM components as ligands for precise delivery. Nanoparticles can be modified with ECM-derived peptides, such as the RGD sequence, which preferentially targets cancer cell integrins. This selectivity improves therapeutic effectiveness at the target areas while limiting systemic negative effects.<ref>{{Cite journal |last=Hwang |first=Jeongmin |last2=Sullivan |first2=Millicent O. |last3=Kiick |first3=Kristi L. |date=2020-02-18 |title=Targeted Drug Delivery via the Use of ECM-Mimetic Materials |url=https://www.frontiersin.org/journals/bioengineering-and-biotechnology/articles/10.3389/fbioe.2020.00069/full |journal=Frontiers in Bioengineering and Biotechnology |language=English |volume=8 |doi=10.3389/fbioe.2020.00069 |issn=2296-4185}}</ref>
-          vii.         Stiffening and Inducing Tumors:
-Elevated ECM stiffness in various cancers can result in mechanical signals that encourage tumor development and spread. As a therapeutic approach, targeting ECM rigidity and the mechanotransducers linked to it can help to disturb the milieu that supports tumor growth.<ref>{{Cite journal |last=Mai |first=Zizhao |last2=Lin |first2=Yunfan |last3=Lin |first3=Pei |last4=Zhao |first4=Xinyuan |last5=Cui |first5=Li |date=2024-05-01 |title=Modulating extracellular matrix stiffness: a strategic approach to boost cancer immunotherapy |url=https://www.nature.com/articles/s41419-024-06697-4 |journal=Cell Death & Disease |language=en |volume=15 |issue=5 |pages=1–16 |doi=10.1038/s41419-024-06697-4 |issn=2041-4889}}</ref><ref>{{Cite journal |last=Yuan |first=Zhennan |last2=Li |first2=Yingpu |last3=Zhang |first3=Sifan |last4=Wang |first4=Xueying |last5=Dou |first5=He |last6=Yu |first6=Xi |last7=Zhang |first7=Zhiren |last8=Yang |first8=Shanshan |last9=Xiao |first9=Min |date=2023-03-11 |title=Extracellular matrix remodeling in tumor progression and immune escape: from mechanisms to treatments |url=https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-023-01744-8#:~:text=Additionally,%20the%20ECM%20shaped%20by%20cancer%20regulates%20immune%20cells%20which%20results%20in%20an%20immune%20suppressive%20microenvironment%20and%20hinders%20the%20efficacy,tumor%20progression. |journal=Molecular Cancer |volume=22 |issue=1 |pages=48 |doi=10.1186/s12943-023-01744-8 |issn=1476-4598}}</ref>
-        viii.         Opportunities for Personalized Therapy:
-Since different diseases cause the ECM to change, knowing which ECM changes can help with the development of particular therapies. It is feasible to improve treatment response and reduce side effects in patients by focusing on these improvements.
-           ix.         Regenerative Characteristics:
-The extracellular matrix (ECM) supplies vital signals for tissue regeneration and repair in regenerative medicine.<ref>{{Cite journal |last=Huang |first=Jiacheng |last2=Zhang |first2=Lele |last3=Wan |first3=Dalong |last4=Zhou |first4=Lin |last5=Zheng |first5=Shusen |last6=Lin |first6=Shengzhang |last7=Qiao |first7=Yiting |date=2021-04-23 |title=Extracellular matrix and its therapeutic potential for cancer treatment |url=https://www.nature.com/articles/s41392-021-00544-0 |journal=Signal Transduction and Targeted Therapy |language=en |volume=6 |issue=1 |pages=1–24 |doi=10.1038/s41392-021-00544-0 |issn=2059-3635}}</ref> Materials made from extracellular matrix (ECM) can be used in drug delivery systems that facilitate healing, act as a natural scaffold for cell proliferation, and enable the regulated release of medicinal drugs.
-§  '''Biocompatible Hydrogels'''
-Hydrogels made from ECM materials offer structural and biochemical support for regulated medication release. These hydrogels can be created to integrate bioactive components that increase cell interactions and allow for prolonged therapeutic effects, notably in tissue engineering and regenerative medicine applications.<ref>{{Cite journal |last=Hwang |first=Jeongmin |last2=Sullivan |first2=Millicent O. |last3=Kiick |first3=Kristi L. |date=2020-02-18 |title=Targeted Drug Delivery via the Use of ECM-Mimetic Materials |url=https://www.frontiersin.org/journals/bioengineering-and-biotechnology/articles/10.3389/fbioe.2020.00069/full |journal=Frontiers in Bioengineering and Biotechnology |language=English |volume=8 |doi=10.3389/fbioe.2020.00069 |issn=2296-4185}}</ref>
-.     (150 pts) Cell proliferation and apoptosis are involved in many physiological and pathological processes such as: repair and healing after injury or inflammation, regeneration of tissues, and the growth, invasion and metastasis of tumors. Describe these processes and how drugs that target apoptotic and/or cell proliferation pathways work in the treatment of tumors and other disorders relating to these processes.

Latest revision as of 04:37, 8 November 2024