Chemotherapeutics and The Cell Cycle Flashcards
What are the steps in the cell cycle?
interphase = G1, S and G2
G1
- growth phase 1 where nutrients are taken up to increase cell size (duplication)
S
- synthesis phase where DNA replication occurs
G2
- growth phase 2
mitotic phase = mitosis and cytokinesis
- mitotis where prophase, metaphase, anaphase and telophase occurs
- cytokinesis where separation of the organelles and cytoplasms occurs
has checkpoints/restriction points to control progression of cell cycle
- detects damaged DNA and initiates repair or apoptosis
What are cyclin dependent kinases (CDKs)? How do they act?
CDKs are protein kinases
- controls cell cycle progression
act by binding to a cyclin, a regulatory protein
- activation via binding
How does CDK act as a hallmarker of cancer?
overactive cyclins or cyclin dependent kinase (CDK) are associated with tumours
- CDK inhibits activation of proteins that would stop cell cycle progression leading to uncontrolled growth
increased cyclin, CDK + reduced CDK inhibitors = disruption of cell cycle regulation
What are the types of tyrosine kinase inhibitors? What are they used to treat?
gleevac - imatinib mesylate
sprycel - dasatinib
treat
- lymphoblastic leukaemia, gastointestinal tumours, etc
How do tyrosine kinase inhibitors work?
tyrosine kinase is a protein/enzyme
TK inhibitors work by
- blocking the phosphorylation of tyrosine on the protein substrate and subsequent activation of the phosphorylated protein
= as the result, the transmission of proliferative signals to the nucleus is blocked and leukemic cell apoptosis is induced
blocks signal transduction
- mechanism of communicating signals in the cell
What are the structural properties of tyrosine kinase inhibitors?
are polar drugs (always)
- contain conjugated nitrogen heterocycles
must be hydrophilic
- contain amide and hydroxyl groups
Why is gleevac useful for treating blood cancers?
exists as an organic salt
- is a mesylate salt meaning it has a methane sulphonate ion
= is water soluble so can treat blood cancers (leukaemia)
What is taxol? What is it used to treat?
taxol - paclitaxel
= has many chiral centres
is used to treat solid tumours via intravenous injection
How does taxol work?
stabilises microtubules (tubulin and actin) against depolymerisation (disassembly)
- prevents segregation and disassembly
= causes mitotic arrest at the G2/M phase (metaphase) or induces apoptosis at G0, G1/S phase
paclitaxel treated cells have defects in mitotic spindle assembly, chromosome segregation and cell division
What is the bioactive form of thalidomide?
S-thalidomide is the bioactive form/teratogenic form
- but individual enantiomers can racemise to each other in vivo
What is thalidomide used to treat? What is lenalidomide used to treat?
thalidomide
- multiple myeloma
- leprosy
lenalidomide
- multiple myeloma = is more effective
What is the purpose of including fluorine in drugs?
increases therapeutic index
- blocks metabolism = e.g hydroxylation by enzymes
- increases lipophilicity of hydrophilic drugs
fluorine has polar hydrophobicity
- is not lipophilic or hydrophilic so increases transport property
fluorine increases acidity
- via electron withdrawing as it is electronegative
What are fludrocortisone, atorvastatin and risperidone? What are they used to treat?
fludrocortisone
- fluorine introduced into cortisol
- treats postural hypotension and adrenal insufficiency
atorvastatin (lipitor)
- treats hypercholesterolaemia
risperidone (risperidral)
- fluorine allows crossing of the blood brain barrier to compete with dopamine
- treats schizophrenia, depression and bipolar disorder
Why is the racemisation of thalidomide the cause of its teratogenicity?
S-thalidomide is teratogenic however as enantiomers can undergo racemisation, the body cannot differentiate between the bioactive and inactive forms
