Chemotherapy Flashcards
What percentage of breast cancer patients get chemo as their primary treatment?
34% of patients with breast cancer have chemotherapy as part of primary cancer treatment
What is consolidated?
Chemical drug induction of remission – prolonged freedom from the disease.
What is adjuvant?
Chemo CTX given for eradication of the disease.used after primary surgery
What is neoadjuvant?
Before surgery – reduces invasive surgery – Locally advanced tumour,Infalmmatory tumours,For larger tumours or those with large amounts of nodal involvement or inflammatory component,neoadjuvant chemotherapy may be used to shrink the tumour before surgey to improve the outcome and preserve remnant breast tissue
What is maintenance?
Prolonged low dose chemical chemo issued to an out patient to extend duration of remission
What is salvage?
CTX/RTX treatment are given after failure of others – control disease progression
What is combination?
More than one chemical agent maximises tumour cell kill
Which drugs work on the M phase
Taxanes,Vinca alkaloids,etposide
Which drugs work on the s phase?
Anti metabolites and topoisomerase inhibitors-
Vinca alkaloids, 5 Fluorouracil,methotrexate,hydroxyurea,doxyrubcin,cytarabine,gemcitabine,etoposide
Which drugs work on the g2 phase?
bleomycin
Which drugs are cell cylcle independent?
platinating agents,alkylating
agents,anthracyclines
What can the risk of recurrence of cancer be reduced by?
using adjuvant
chemotherapy
What is adjuvant?
After primary surgery
What is neoadjuvant?
Before surgery
How many ppls chemo fails and due to what exactly?
50% due to intrinsic and
acquired multiple drug resistance.
What are the risk factors associated with the onset of a resistant phenotype?
genetic predisposition such as mutation in a and b tubulins, and BRCA1/2; induction of expression of multi drug resistance MDR, alteration in spindle assembley checkpoints,cell cycle proteins and apoptosis.
What are mitotic inhibitors and which stage do they affect?
Disrupt the M phase of the cell cycle – leading to cell arrest.
Give an example of a mitotic inhibitor
Taxanes – paclitaxel,doxcetaxel,cabzitaxel. – Extracted from the Pacific yew- t.brevifola bark. 12- slow gorowing trees required for 1 patient.
What is paclitaxel and example of and what does it do?
Taxane . Microtubule stabiliser – cats during the telophase of the M phase – bind to subunit of tubulin – the building block of microtubules.The resulting microtubule/paclitaxel complex does not have ability to disassemble – blocking progression into mitosis and causing prolonged activation of the mitotic checkpoint.This triggeres apoptosis or reversion to the g0 phase of the cell cycle without cell division taking place
What is its Mr
RMM is so bad, 15-h bond acceptors.
What is its class and what does that then mean
it is class 5 so poorly permeable and
poorly soluable of the biopharmaceutical classification, not ideal for oral delivery
What are other taxanes?
Doxetaxel, cabzitaxel
What are the 3 points for the formulation and delivery of paclitaxel?
- Given via IV route
- Fromulation with cremophor(polyoxyl castor oil)improves its water solubility –
but cremaphor has the tendency to cause severe allergic reactions so, pre- administration of steroids and anti histamines is recommended. Cremaphor can form micelles in plasma,trapping paclitaxel and preventing distribution to cancer cells. - New approach for paclitaxel formulation sees it complexed with albumin to create nanoparticle colloidal systems.This solubalises paclitaxel which accumulates in tumour beds.No cremaphor needed so avoid sensitivity issues.
What are the side effects of taxanes specifically?
May cause peripheral neuropathy -numbness,tingling,paraesthesia and a burning pain in a stocking glove distribution. This is related to the effects on microtubule function in the nerve cells and other healthy tissue. Stress hormones were shown to arrest cells in the G0/G1 phase,which would serve to substanciate the decrease in paclitaxel efficacy – which taregts sphase.
What is another type of mitotic inhibitor?
And where does it act specifically? – Vinca alkaloids – Vincristine – Act during the metaphase,inhibiting microtubule assembley and casuing cell arrest – microtubule destabilisers.
Give a list of examples of alkylating agents
Cyclophosphamide
What is the mechanism of restsiance of an alkylating agent?
Pro drug converted to
phosphoramide mustard
- Targets S phase
- Cross links guanine babses by binding alkyl groups
- DNA stands are unable to uncoil so cells can no longer perform mitosis
- Also adds methyl/other alkyl groups onto other molecules – casuing miscoding of
DNA and cell apoptosis.
- Mechanism of resistance = Increased ability to repair DNA defects,decreased cellular permeability to the drug,increased glutathione synthesis,inactivation of alkylating agents through conjunction reaction.
Give 2 examples of anti tumor anti biotics:
Doxorubicin, epirubicin
How does doxorubicin work?
Forms complexes with DNA by intercalation between
base pairs.
-Inhibits topisomerase II activity,preventing resealing of DNA strands and inhibiting DNA replication.
-May also inhibit polymerase activity affecting regulation of gene expressin and produce ROS causing free radical damage to DNA and triggering apoptosis.
How does epirubicin work?
- Most active during the sphase.
- Forms complexes with DNA by intercalation between base pairs
- -Inhibits topoisomerase II activity,preventing the resealing of DNA strands and
inhibiting DNA replication - Also inhibits nucleic acid and protein synthesis
What are antimetabolites? What are the main enzymes affected
Thymidylate synthase and dihydrofolate reductase enzymes are involved in the production of thymine – a dna base. If these enzymes are disrupted,pyrimidine synthesis will cease and as a result – so will dna syntheisis.
Explain what 5fu is ?
-Flurorouracil
- Bio- transformed to ribosyl and deoxyribosyl derivatives
- Targets the S phase
- fdUMP inhibits thymidine synthase – therefore inhibits thymidine synthesis,preventing DNA synthesis.
- 5- Fluroridine triphosphate is incooperated into RNA,interfering with RNA function
Explain how methotrexate works.
- Targets S. phase
- Inhibits dihydrofolate reductase,preventing DNA synthesis.
- Mechanism of resistance – Decreased drug transportation into the cell
- Altered dihydrofolate reductase enzyme with a lower affinity for methotrexate
- Quantitive increase in dihydrofolate reductase enzyme concentration in the cell –
gene amplification and increased message.
Explain what a topoisomerase inhibitor is?
Top 1 – cleaves one strand of DNA and relaxes DNA coil during replication Top2 – Cleaves 2 strands of DNA and relaxes DNA supercoil during replication.
Explain what a camptothecins
– top1 inhibitor is and what the 2 examples of it are? TOPOTECAN and IRINOTECAN – Targets S phase
- Interferes with Top 1 activity preventing re- ligation of single strand breaks
causing lethal double stranded breaks in dna and apoptosis.
What is an etoposide – top 2 inhibitor?
- Targets the S phase
- Interferes with Top 2 activity, inhibiting DNA – re ligation .This causes critical
errors in DNA synthesis at the pre – mitotic stage of the cell division, leading to apoptosis.
Protein kinases carry out post translational changes to proteins –
serine,threonine,tyrosine and histidine amino acid residue, which affects their eactivity and properties.
PHOSPHORYLATION IS TH ETRANSFER OF PHOSPAHTE GROUP FROM atp TO AMINO ACIDS RESIDUE ON THE PROTEIN – GIVES structural and or – conformational changes to the protein,activating or deactivating it.
What is egfr? A family of 4 receptor tyrosine kinases
EGFR(ErbB1,ErbB2, ErbB3,ErbB4) and Her 1,2,3,4.They have extracellular receptor,transmembrane- spanning domain,kinase domain and ATP binding domain.
What is an example of a monoclonal antibody against HER-2?
TRASTUZUMAB!!
40. What does it work on and what is its mechanism of action?It is a
recombinant,himanised Ig1 mAb against egfr her-2 .
iT BINDS TO THE XTRACELLULAR LIGAND BINDING DOMAIN,and blocks the cleaving of extracellular domain of her 2.This prevents the phophorlyation of p95 – which is used to signal transduction pathways.
- Inhibition of MAPK3 and PI3K pathways lead to an increase in cell – cycle arrest
and the suppression of cell growth and proliferation.
- Transtuzumab also mediates the activation of antibody dependent cell mediated
cytotoxicity ADCC by attracting the immune cells – such as natural killer NK cells
to tumour cites that over express HER-2.
- This disrupts downstream activity and reduces cell growth and division.
What must trastuzumab be given as in terms of formulation and why?
Must be given as a sC injection( although there are issues with SC injections – training and painful site) it gives good absorbtion and has arapid onset of action and is uselful if the pt is vomiting or unresponsive.
What is the problem with costing and what is its hazard ratio?
Trastuzumab halves the risk of relapse (hazard ratio 0.54) but expesnive to generate - £25,000 per year.
What is an example of a tyrosine kinase inhibitor?
Imatinib
How does it work?
Binds to ATP binding site of the kinase,interacellulary,interfering
with phosphorylation of epidermal growth factor receptor EGFR and ERBB2.
- Disrupts downstream activity and reduces cell growth and division.
What are its chemical reservations?
meets requirments of a good drug -less than 500
Da,Lop P is grear than 5.2, 2 H bond donors and 6 H bond acceptors.It is class 1 so very soluable. So ideal for oral delivery – as per british pharmaceutical classification system.
Giver other biologics that can also be used?
Lapatinib and everolimus
How does laptinib work?
an inhibitor of the intracellular tyrosine kinase domain of
both HER 2 and EGFR receptors.It is useful in HER 2 ppositive BRCA
How does everolimus work?
s a mTOR inhibitor, reduces the activity of effectors downstream which leads to a blockage in the progression of cells from G1 to S phase and as a result inducing cell growth arrest and apoptosis.Useful in post menopausal women with ER positives, HER 2 negative locally advanced or secondary breast cancer whose cancer has progressed or recurred with hormone therapy
Why don’t we just give it all at once and get it over with???
CUZ ITS TOXICCCC!!!!
Rh-G-CSF = Recombinant human Granulocyte colony stimulating factor
Stimulates the bone marrow to produce granulocytes and release them into the blood stream. Stimulates survival, proliferation, differentiation & function of neutrophils and neutrophil precursors
Filgrastim (e. coli) , lenograstim (CHO), can be PEGylated.
Primary prophylaxis: start >24hrs post chemo and continue until the expected nadir has passed (usually given days 5-9 or 2-11)
Now available as a biosimilar
