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Oncology > CANCER CHEMOTHERAPY 🌈 > Flashcards

CANCER CHEMOTHERAPY 🌈 Flashcards

1
Q

5 Targets for anti cancer agents

A
  1. DNA
  2. MIROTUBULES
  3. EPIGENETICS
  4. CELL SIGNALLING
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2
Q

Drugs that target

  1. DNA
A

Anthracyclines
Camtothecin
Nitrogen mustards
Cisplatin
Temozolomide

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3
Q

Drugs that target

  1. Microtubules
A

Taxanes

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4
Q

Drugs that target

  1. Metabolism
A

Methotrexate, 5-flurouracil

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5
Q

Drugs that target

  1. Epigenetics
A

Azacitidine
Decitabine
Virinostat
Romidepsin

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6
Q

Drugs that target

  1. Cell signalling
A

Tyrosine kinase Inhibitors

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7
Q

Phases of the cell cycle

A

S phase: DNA is synthesised and replicated

M phase: chromosomes are seperstes between 2 new nuclei = separated by 2 so callee Gap phases: G1 and G2

G1, S and G2 = collectively are the Interphase ( period between one mitosis and the next)

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8
Q

Why do chemotherapy have specificity for cancer cells in the S phase?

A

Cancer cells grow more rapidly, therefore have a higher requirement for NUCLEOTIDES in Dna and Rna synthesis

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9
Q

Specificity in cancer cell- production of DNA and Rna

A

Cancer cells favour DE NOVO SYNTHESIS

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10
Q

What is an essential metabolite?

A

Necessary for the growth of the organism, but cannot be synthesised by cells of that organism

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11
Q

Name one essential metabolite

A

Folic acid,

cannot be made by mammalian cells

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12
Q

Anti-metabolite:
METHOTREXATE

MOA

A

Dihydrofolaye reductase (DHFR) INHIBITOR

DHFR = KEY IN REGENERATION OF FOLIC ACID COFACTORS REQUIRED FOR DNA SYNTHESIS.

  • folic acid cofactors are one C donors (formyl or methyl)
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13
Q

Synthesis of Folic acid and Cofactors

A
  1. Folic acid -> dihydrofolic acid
    (Gets reduced by adding H+ in the 7- or 8- positions)
  2. Dihydrofolic acid -> tetrahydrofolic acid (By DHFR) (gets catalysed again (2H+) by DHFR at 5 and 6 positions
  3. (De novo): formate group is donated = the Cq donar is converted to FH2 and has to be regenerate in a cycle.

MTX BLOCKS THIS CYCLE = BLOCKS DHFR

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14
Q

MTX POLYGLUTAMATES

Why is folinic acid given with MTX?

A

To rescue the gut and bone marrow cells (so normal cells can recieve folic acid)

In normal cells: we have low levels of MTX POLYGLUTAMATE and folinic acid cab displace them (act as a carbon donar)

In cancer cells: have high levels of MTX POLYGLUTAMATE which binds really tightly to the DHFR and stop it from acting.

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15
Q

Why is 5FU a prodrug?

A

5FU metabolised by enzymes therefore bioavailability is LOW.

CAPECITABINE ( prodrug)

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16
Q

Which enzyme is involved in Pyrimidine biosynthesis?

A

Thymidylate Synthetase

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17
Q

Role of Thymidylate synthetase in Pyrimidine biosynthesis?

A

TS breaks double bond in deoxyUridine (dUMP) molecule.
(TS = basic residue and Thiol group)
1. Thiol group = attacks BETA carbon on DUMP and gets methylated.
2. Basic group, removes the H+ (acidic H) which then regenerates the double bond again = this allows for the release of the Thiol and regeneration of the enzymes active site).

Process:
dUMP is methylated at the 5 position to get dTMP (procurser)
Now it needs another 2 phosphate group to get incorporated into DNA.

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18
Q

Process of PURINE SYNTHESIS

A
  1. Firmly group is donated from N10-formyl-FH4 = to form an amide.
  2. Which then cyclists and forms inosinate-> which is converted to purines (DNA POLYMERASES)

** IF WE BLOCK N10-formyl-FH4, we block this synthesis.

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19
Q

What happens at the metaphase?

A

Spindle fibres align the paired chromosomes (sister chromatids) along the middle of the cell nucleus = leading the process of the cell dividing. This is where the microtubules come out.

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20
Q

Microtubule structure

A

Spindles form by polymerisation.

+end = from Alpha tubulin
-end = from beta tubulin

21
Q

2 classes of Antimiotic drugs

A

Taxanes
Alkaloids

22
Q

Difference between MOA OF ALKALOIDS and TAXANES

A

Alkaloids =
Block cells at the metaphase/anaphase Junction of mitosis. By destabilising microtubules

Taxanes =
Also arrest cells at mitosis but
PROMOTE the polymerisation of purified tubulin, causing stabilisation and bundling of microtubules

23
Q

S.A.R of Taxanes

A

Diterpenoid compound.
Taxane ring + side chain linked to taxane ring at
C13 (essential for anti-tumour activity)

24
Q

Taxanes: how they stablise microtubules against depolymerization

A

Taxanes stabilise microtubles by binding preferentially to assembled purified b-tubulin with an exact 1:1 stoichiometry (taxanes join between b and a subunits)

Therefore stop the uncontrolled cell division of cancer cells by forming extremely stable by non functional microtubules.

25
Q

RESISTANCE: taxanes

A

Due to change in composition of microtubules, with increased expression of bIII tubulins

(Changes to a and b binding site)
= taxanes can bind there if this changes)

26
Q

Non-specific chemotherapies:

Inducing DNA damage-

Include 3 classes

A
  1. Toposiomerase 1 Inhibitors
    = IRINOTECAN
  2. Topoisomerase 2 Inhibitors
    =Epipodophyllotoxins
  3. Alkylating agents
    = nitrogen mustards,
    Platinum complexes
    Nitrosoureas
    Triazenes
27
Q

How does DNA relaxation take place?

A

-type 1 topoisomerases relax DNA by cutting 1 of the DNA strands

  1. DNA catenation=decatenation are crucial steps in delivery of DNA to daughter cells
  2. Catenated DNA contains interlocked helicrs and must be relaxed by topo 2 enzymes cleaving both strands
28
Q

How do Anthracyclines work?

A

Inhibit DNA relegation through yhr stabilisation of transient DNA-TOP2 complexes by binding at DNA-TOP2 interphase and forming DNA-TOP2-anthracycline complexes

29
Q

Anthracylines:
Doxorubicin, Etoposide

moa

A

Produce double bond strand breaks = if not repaired get cell apoptosis.

30
Q

Anthracylines (DOXO)

RESISTANCE:

A

Due to overexpression of P glycoprotein , multiprogramming resistance associated protein (MRP1) and breast cancer resistant protein

31
Q

Alkylating agents: nitrogen mustards

A

Cyclophosphamide

32
Q

Alkylating agents:
Platinum complexes

CISPLATIN

Moa

A
  1. Taken up by cell by either
    A. PASSIVE diffusion
    B. Organic cation transporter
    C. Metal transporter (cu)
  2. Cl concn: much lower inside the cell
    More susceptible to exchanging a Cl for a WATER molecule.
    whereas outside the cell = more Cl-, therefore therefore if Cl is ever lost, will be replaced by snother Cl.
  3. Cation = active form = interacts with DNA and produces disruptions to shape of DNA. Causing apoptosis.
  4. Exit=
    A. Efflux ATP
    B. GLUTATHIONE EFFLUX
33
Q

Resistance of CISPLATIN

(Alkylating agents= platinum)

A
  1. Decrease diffusion into cell
  2. Increase efflux
34
Q

Alkylating agent:

Temozolomide (a prodrug)

Moa

A
  1. During DNA replication, O6-methylguanine in the template strand will result in mismatched thymine in the newly synthesised strand.
  2. Mismatched repair (MMR) processes then remove the DNA containing the mismatched Thymine, only for the NDA polymerase to reinsert thymine opposite to O6-methylguanine
  3. Cycle stops. Resulting in DNA strand breaks (nicks) which result in apoptosis
35
Q

What is MGMT enzyme?

A

O6- methylguanine methyltransferase
(Overexpressed in cancer cells)

  1. Gets flipped out of thr DNA double helix and into the active site of thr enzyme (MGMT)
  2. In this active site, there is a cyctrine residue which attackd the methyl group (Me).
  3. The Ch3 (methyl) group is transformed into O6- methylguanine onto the thiol group.
    THIS IS COVALENTLY BONDED.
  4. THEREFORE, can’t remove methyl anymore. Big insult to cell! Cell needs to resynthesis of enzyme again.
36
Q

New cancer therapeutics:

Epigenetic targeting agents:

A
  1. History deacetylase (HDAC) INHIBITORS
    = vorionostat (Lymphomas)
  2. DNA methyltransferase (DNMT) INHIBITORS
    = azacitidine (leukaemias (AML))
37
Q

Epigenetic and nucleosomes

Revision

A
38
Q

DNA methylation

A
39
Q

DNA methylation and azacitidine

A

Glutamatic acid gets rid of this H+, we get methylation.

-covalently bound
…

40
Q

Resistance in azacitidine

A

Resistance to DNMT inhibitor-

Increased ration of CDA and dCK corresponds to Poorer treatment outcomes.

** both azactidine and decitabine require activation via their triphosphates (CDA and dCK)

41
Q

Histone lysine deacetylation (HDAC) epigenetic erasers

A
  • lysine groups of Histones are cations so form strong interactions with the avionics DNA phosphates
  • acetylation (by histone acetyltransferases -HATs) produces amodes and so removes the positive charge = and so the ionic interaction)
  • the reduced histone - DNA interaction allows the structure to open up and access of the DNA transcription factors.
42
Q

Receptor kinase ihbitiors: kinases catalyze phosphorylation

Receptor tyrosine kinases (RTKs) include:

A
  1. Insulin-like growth factor (IGF-1R)
  2. Platelet derived growth factor (PDGFR)
  3. Epidermal growth factor (EGFR)

THESE RECEPTORS TAKE A MESSAGE GROM OUTSIDE THE CELL AND PASS IT ACROSS THE MEMBRANE TO THE NUCLEUS

43
Q

Receptor kinase Inhibitors

Names and class

A
44
Q

Role of EGFR in cell signalling

A
  1. EGFR (ligand) binds
  2. The 2 receptors then come together (dimerisation)
  3. This phosphorylates a tyrosine residue = inactive

When the ligands bind you get dimerisation = activation

45
Q

How do tyrosine kinases Inhibitors work

A

Takes tyrosine residue which adds a phosphate group = this kicks off a cascade of RAS, JAK, etc.

== IF WE STOP THE TYOSINE KINASE PART, we can stop the phosphorylation and hence the cell proliferation.

46
Q

How does Getifinib bind to the EGFR TK?

A

It binds at the ATP-binding site: QTP binding site has a key Lysine (K745).

THIS DRUG BINDS AT THE SAME SITE AS THE ATP UNIT, WHICH IS A PHOSPHATE DONAR.

therefore, the Tyrosine doesn’t get phosphorylated = no cascade of events which lead to no cell proliferation!

47
Q

Resistance to Getifitinib?

A

63% of patients with resistance have a T790M mutation.

48
Q

Dabrafenib/ Trametinib combination?

A

Combo of BRAF (D)+ MEK (T) INHIBITORS are more effective than BRAFi alone!

For treatment of malignant melanoma.

Oncology (15 decks)

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