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