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MITOTIC INHIBITION
ID STUDENT’S NAME
USTHBI4- NGÔ PHƯƠNG DUNG
USTHBI4-059 NGUYÊN THI MINH HƠI
USTHBI4- KHĂC THI HƯƠNG
USTHBI4- PHAM MY LINH
USTHBI4- TRÂN THANH TU
Contents• Brief information about Mitosis• Mechanism of mitotic inhibition• Application of some mitotic inhibitors• Taxanes
• Paclitaxel• Docetaxel
• Angiogenesis inhibition• Telomerase inhibition
• Mitosis : a part of cell cycle which chromosomes are separated into 2 identical sets.• Occur : Cell nucleus.• Cytokinesis : Cytoplasm,
organelles and cell membrane are divided into new cells with same components.
ProphaseChromosomes condenseNuclear envelope disappearsChromosomes connect to microtubules
Metaphase All chromosome are aligned at metaphase plate
AnaphaseSister chromatids are separate.Chromosomes are pulled to opposite poles.
TelophaseCell membrane completes constrictionNuclear envelope reforms
Mitotic Inhibition
• Mitotic inhibitors: drugs that inhibits Mitosis or cell division.
• Mechanism of mitotic inhibitors:• Inhibition of polymeration process
of microtubules (structures that pull the cell apart when it divides)
• Stopping nutrient supply• Making chromosomes are
abnormal (shorten).
Roles of Microtubules
Microtubules provide the structure and machinery for chromosome segregation during mitosis
Function
Inhibitors inhibits the Polymerization Process
Interruption of nutrient supply
Using inhibitors to cut off the nutrient (e.g. blood) supplied to growth phases (G1, G2)
Natural agent : from the genus Taxus (yews)Taxanes
Mechanism of action: Inhibiting microtubule polymerizationDisrupting the microtubule functionPreventing cells from
entering mitosis.Stimulating apoptosis, or programmed cell death.
Side effects:- Bone Marrow Suppression- Nausea and Vomiting- Hair Loss- Peripherial Neuropathy- Peripherial Neuropathy
PaclitaxelUsed to treat lung cancer, ovarian cancer, breast cancer, and advanced forms of Kaposi's sarcoma.
Docetaxelused to treat breast, ovarian, and non-small cell lung cancer
from the periwinkle plant Catharanthus roseus (basionym Vinca rosea) and other vinca plants.
Vinca alkaloids
Mechanism: bind to tubulin at the forming end of microtubules and disrupt spindle assembly.
Side effects: nausea, vomiting, fatigue, headache, dizziness, peripheral neuropathy, hoarseness, ataxia, dysphagia, urinary retention, constipation, diarrhea, bone marrow suppression, alopecia and phlebitis at the infusion site.
Including: vinblastine, vincristine, vindesine, and vinorelbine
Vinblastine: used to treat leukaemia, Hodgkin's lymphoma, non-small cell lung cancer, breast cancer and testicular cancer .
Targeting Angiogenesis in Cancer Therapy
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels.
Blood vessels are composed of three main cell types
Angiogenesis was mainly regulated by three angiokinase pathwaysThree signaling molecules
Vascular endothelial growth factor (VEGF) Platelet-derived growth factor (PDGF)Fibroblast growth factor (FGF)
Activate the receptor tyrosine kinases on endothelial cells, pericytes and smooth muscle cells to initiate important pro-angiogenic signaling cascade.
VEGF and FGF PDGF PDGF and FGF
• Tumors need a blood supply to provide the oxygen and other essential nutrients they require in order to grow beyond a certain size.
• Angiogenesis is also required for the spread of a tumor, or metastasis.
Tumors cannot grow beyond a certain size or spread without a blood supply, scientists are trying to find ways to block tumor angiogenesis.
Some kind of Angiogenesis Inhibitors were used to treat Cancer
in HumanOrigin Mechanism Cancer How to use?
Bevacizumab (Avastin)
Recombinant humanize monoclonal antibody
Inhibiting VEGF-A Colorectal cancer, kidney cancer, and lung cancer.
Injected into vein
Sorafenib (Nexavar)
Small molecular inhibitor(C21H16ClF3N4O3)
Sorafenib is a Kinase Inhibitor (VEGFR and PDGFR)
Kidney cancer, liver cancer, and thyroid cancer
A pill was taken by mouth
Ramucirumab (Cyramza)
Fully human monoclonal antibody (IgG1)
Binding to VEGFR2 it works as a receptor antagonist
Stomach cancer Injected into a vein
Side effects of Angiogenesis Inhibitors
• High blood pressure• A rash, dry, itchy skin• Diarrhea• Fatigue• Low blood counts• Problems with wound healing or cuts re-opening• Rarely, angiogenesis inhibitors may cause serious bleeding, heart
attacks, heart failure, or blood clots.
Telomerase Inhibition
What is the Telomerase?
• Telomere: The sequences of DNA extending at the ends of chromosomes.• Telomerase: a ribonucleoprotein
that maintains the lengths of chromosomal ends.• 2 major components of the
telomerase holoenzyme:• Telomerase reverse transcriptase
(TERT) protein subunit • Telomerase RNA (TR) component
Telomerase in Cancer Therapy
• Telomerase is expressed in germline, embryonic stem cells and most somatic stem cells, barely detectable in the great majority of adult somatic cells
• In actively dividing somatic cells, the telomeres shorten with each cell replication.
• Telomerase is overexpressing in human cancer cells (approximately 90% compare with normal cells)
• Analysis of telomerase activity has potential as a diagnostic marker of cancer
• Inhibition telomerase activity can leads to:• a marked reduction in cellular viability• induces apoptosis of cancer cells
• Relative low risks
• The inducing of some effective drug
Targeting Telomerase in Cancer Therapy