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Nanocell: Mechanism of action

Explore the mechanisms and applications of chemotherapeutic agents, including Nanocell technology, in treating liver cancer and overcoming drug resistance problems. Learn about FTY720, doxorubicin, 5FU, and their interactions with DNA for effective treatment.

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Nanocell: Mechanism of action

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  1. Nanocell: Mechanism of action Soraya Aroonvilairat Inter-U program, AIT

  2. Scope: Mechanism of Nanocell • Mechanisms of chemotherapeutic agents • Conventional drugs for liver cancer& drug resistance problems • Mechanisms of FTY720, doxorubicin& 5FU

  3. http://www.ovc.uoguelph.ca/BioMed/Courses/Public/Pharmacology/pharmsite/98-409/Cancer/Anticancer_drugs1.htmlhttp://www.ovc.uoguelph.ca/BioMed/Courses/Public/Pharmacology/pharmsite/98-409/Cancer/Anticancer_drugs1.html

  4. Types of chemotherapeutic drugs (1) • Antimetabolites • Structurally related to naturally occurring compounds (vitamins, amino acids, nucleotides) • Result: interfere DNA & RNA synthesis, cell proliferation • Covalent DNA-binding drugs (Alkylating agents) • Drugs (electrophilic) covalently bind to alkyl groups of bases of DNA & protein (nucleophilic) • Result: single strand break, base mispairing, cross linkage

  5. Types of chemotherapeutic drugs (2) • Noncovalent DNA-binding drugs • Intercalating drugs forming tight drug-DNA interaction • Free radical damage cause single strand break • Drugs affecting endocrine function • Steroid hormones (estrogen) or their antagonists • Inhibitors of chromatin function • Drugs which disrupt the chromosomal dynamic necessary to carry out DNA replication and mitosis • 2 subgroups: topoisomerase inhibitors & microtubule inhibitors

  6. Cisplatin • IUPAC name : dichloroplatinum;azanide • Chemical formula : Cl2H4N2Pt • Platinum based chemotherapeutic drug & Alkylating agent • Application: solid tumors (testis, ovary, head & neck, bladder)

  7. Cisplatin-DNA interaction Inter-strand cross-links Intra-strand adduct N7-guanine http://www.iupac.org/publications/pac/1987/pdf/5902x0181.pdf

  8. Mitomycin C • Chemical formula : C15H18N4O5 • Antitumor antibiotic, alkylating agent • Application: malignant neoplasm (oral cavity, pharynx, breast, and urinary bladder) • Mechanism: binding to DNA, cross-linking, inhibit DNA synthesis

  9. What are the problems of chemotherapeutics usage • Side effects: nausea & vomiting, hair loss, bone marrow suppression, mouth sores, skin changes, diarrhea • Drug resistance: • Decrease drug accumulation ( drug influx, drug efflux) • Altered drug metabolism • Altered drug targets • Increased repair of drug-induced damage

  10. ABC transporters (P-gp) Mechanisms of drug resistance Altered drug accumulation within cells • Binding of drugs • Activate ATP-binding domain • ATP hydrolysis causes drug release into extracellular space • Mutation of receptors or transporters involving drug uptake Annu Rev Med 53:615-27, 2002

  11. 100 nm 200 nm Nanocell design for liver cancer Lipid vesicle with integrated antiangiogenics Fast release kinetics Nanocore Loaded with Chemotherapeutics Slow release kinetics

  12. Anti-angiogenic: FTY720 • IUPAC name: 2-amino-2-[2-(4-octylphenyl)ethyl] propane-1,3 diol • Synthetic analogue of natural compound derived from fungus Isaria sinclairii. • Originally developed as novel immunosuppressant in organ transplantation • Sphingosine analogue

  13. FTY720: sphingosine analogue http://www.postech.ac.kr/chem/skc-lab/research/lipidomics.htm

  14. Angiogenic process • Angiogenesis induced by VEGF (tumor) • Degradation of basement membrane • Invasion & migration of endothelial cells to tumor • Elongation of new vessel by proliferation • Vessel maturation by synthesis of ECM www.amplab.de/3D-Images/angiogenesis-scheme.gif

  15. FTY720: mechanism of action • FTY720 phosphate (FTY-P) acts ahigh-affinity agonist at the G protein-coupled sphingosine 1-phosphate receptor • Decreased Rac expression of tumor cells (related to endothelial cells migration, chemotaxis) • Inhibited VEGF expression induced vascular permeability (anti-angiogenesis)

  16. FTY720: mechanism of action http://www.postech.ac.kr/chem/skc-lab/research/lipidomics.htm

  17. Doxorubicin (Adriamycin) • Chemical formula : C27H29NO11 • Cytotoxic anthracycline antibiotic • Noncovalent DNA binding drug • Application: treatment of solid tumors (breast, ovarian, lymphoma, HCC, soft tissue sarcoma)

  18. Doxorubicin: mechanism of action • DNA intercalation: binding to DNA, inhibit the progression of topoisomerase II which unwinds DNA for transcription,consequent in cell cycle disruption & cell death • Free radical damage involving reactive oxygen species (ROS) ss breakage

  19. Doxorubicin-DNA complex http://chemistry.clemson.edu/ChemDocs/

  20. 5-Fluorouracil (5-FU) • IUPAC name : 5-fluoro-1H-pyrimidine-2,4-dione • Chemical formula : C4H3FN2O2 • Anti-metabolite drug • Pyrimidine base analogue • Application: treatment of solid tumors (breast & colon carcinoma)

  21. 5-FU: pyrimidine analogue • 5-FU resembles the pyrimidine bases uracil and thymine (components of RNA & DNA) Uracil Thymine 5-Fluorouracil

  22. FdUMP FUTP Inhibit thymidylate synthase Mistakenly incorporate to RNA Depletion of dTMP (required for DNA systhesis) alter RNA processing and protein synthesis Apoptosis 5-FU: mechanism of action 5-FU

  23. Summary • Nanocell is designed to solve the problems of side effects & drug resistance • Design of nanocell: anti-angiogenics (outer), chemotherapeutics (inner) • Anti-angiogenesis of FTY720: via Rac-VEGF mediated pathway • Chemotherapy of Doxorubicin: DNA intercalation, 5FU:apoptosis, alter RNA processing & protein synthesis

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