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Pharmacology (Semester 6) > 5.1 Cancer Chemotherapy > Flashcards

5.1 Cancer Chemotherapy Flashcards

1
Q

What is the trade name of Imatindib and what is its target?

A

STI571 - Glivec ➡ “magic bullet”

It targets the Bcr-Abl tyrosine kinase inhibitor (mutation seen in children with CML)

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2
Q

Give 3 benefits of Imatinib

A
  • Tumour selective
  • More efficacious than other drugs
  • Fewer side effects
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3
Q

Describe the Structure of DNA (4)

A
  • Nucleotide = sugar phosphate-base
  • DNA = double helix of nucleotides
  • Purines = Adenine and Guanine
  • Pyridimines = Cytosine and Thymine (Uracil in RNA)
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4
Q

In the body which 2 sites have the fastest cell turnover?

What is the implication of this for cancer growth

A

The gut and the bone marrow

Fast cancer growth meaning diagnosis often occurs during late stage/ after metastisis

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5
Q

Why is chemo treatment given every 21 days?

A

To achieve best possible selectivity

This will continue targeting/damaging cancerous cells BUT allow the normal healthy cells to recover

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6
Q

What is the ‘fractional cell kill hypothesis’

A

states that a defined chemotherapy concentration, applied for a defined time period, will kill a constant fraction of the cells in a population, independent of the absolute number of cells.

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7
Q

What are the 3 classifications of tumours according to chemo-sensitivity

A

Highly Sensitive

Modest Sensitivity

Low Sensitivity

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8
Q

Give an example of 2 tumours which are highly sensitive to chemo

A
  • Lymphomas
  • Germ cell tumours
  • Small cell lung
  • Neuroblastoma
  • Wilm’s tumour
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9
Q

Give an example of 2 tumours which are moderately sensitive to chemo

A
  • Breast
  • Colorectal
  • Bladder
  • Ovary
  • Cervix
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10
Q

Give 2 tumours which have low sensitivity to chemo

A
  • Prostate
  • Renal cell
  • Brain tumours
  • Endometrial
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11
Q

Give 4 drug classes which target tumours at a cellular level and state where each acts

A

Alkylating agents: DNA itself

Antimetabolites: DNA synthesis

Intercalating agents: DNA transcription and translation

Spindle poisons: Mitosis

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12
Q

At what 2 phases of the cell cycle are alkylating agents most effective

A

Max effect during ‘S’ phase due to greastest replication + large numbers of unpaired strands

OR

G1 when DNA synthesis enzymes are being transcribed. Disruption here will reduce number of enzymes, thus interfering with the process of cell division

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13
Q

What drug class are Platinum Compounds part of and give their MoA

A

Alkylating agents ➞ directly modify DNA structure

Undergo chemical reactions with DNA to form platinated inter-strand and intra-strand adducts.

This interferes with DNA replication and RNA transcription ➞ inhibits DNA synthesis

(Inhibition of replication = main cause of cell death)

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14
Q

What are the 2 most common platinum intra-strand adducts?

A

55% G-G and 30% A-G adducts

(with intra-stand linking being most favoured)

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15
Q

What are DACH platinum adducts, and how do they differ from platinum adducts?

A

DACH = diaminocyclohexane

DACH platinum adducts are bulky and thought to be more effective in inhibiting DNA synthesis than platinum adducts

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16
Q

Give the MoA of antimetabolites

A

Antimetabolites are structurally related to precursors involved in DNA synthesis.

They act to interfere with the production of the purine or pyearimidine nucleotides by acting as a direct competitive analogue in DNA or RNA synthesis

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17
Q

Give 2 examples of Antimetabolites and what each targets

A

1) Methotrexate: potent inhibitor of Dihydrofolate Reductase (DHFR) which interferes with folate metabolism
2) 5-Fluorouracil: pyearimidine analogue of the base uracil

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18
Q

Give the MoA of 5-Fluorouracil

A

5-FU is activly transported into the cell through the same mechanism as uracil (uracil analogue)

5-FU is converted into 5-FdUMP (active form of drug), which competes with dUMP for a binding site on Thymidylate Synthase.

Once bound 5-FdUMP combines with a co-enzyme to produce a stable complex that is irreversible. This complex inhibits the enzyme causing ‘thymidine-less cell death’

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19
Q

What is folate necessary for?

A

Folates are vital for production of purine and thymidilate nucleotides which enables DNA and RNA synthesis.

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20
Q

How is Folate metabolised?

A

Folate is activly taken into cell and converted in to a polyglutamate. The polyglutamated folate is reduced in two steps by DHFR to produce a tetradyhdrofolate

This then acts as a co-factor to covert DUMP into DTMP by the Thymidylate Synthase enzyme.

DTMP contributes to the production of the purines and pyearimidines required for DNA and RNA synthesis

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21
Q

Give the MoA of Methotrexate

A

Methotrexate is structurally similar to folic acid. It is actively transported into the cell and polyglutamated

Methotrexate alone has a much higher affinity than folate for DHFR. The polyglutamated form also has a very long half-life within the cell and high affinity for DHFR

Both Methotrexate alone and its polyglutamated form act to reduce the metabolism of folate which reduces nucleotide production (mainly thymidine)

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22
Q

During what phase of the cell cycle are anti-metabolites most effective?

In which case would therefore be least effective?

A

Most effective during the ‘S’ phase: period of maximal DNA synthesis

They have less effect during the resting state hence are not indicated for use in low growth malignancies

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23
Q

Describe the structure of microtubules

A

Protein subunits, α and β tubulin

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24
Q

How does spindle formation occur during DNA replication

A

1) chromosome align at the metaphase plate
2) spindle microtubules depolymerize, moving sister chromatids toward opposite poles
3) nuclear membrane re-forms and cytoplasm divides

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25
Q

What are the 2 targets of microtubule-binding agents

A

1) Inhibit polymerisation
2) Stimulate polymerisation and prevent depolymerisation

26
Q

Give 2 types of spindle poisons/ microtubule inhibitors and what each targets

A

1) Vinca alkaloids: inhibit polymerisation of tubulin
2) Taxanes: promote and stabilise formation of tubulin polymer into microtubules

27
Q

Give 2 examples of Vinca alkaloids

A

vincristine and vinblastin

28
Q

Give the MoA of Vinca alkaloids

A

Bind to the β-tubulin subunit inhibiting formation of the microfilaments that make up the microtubule

Results in inabiliy for mitotic spindle to form and the cell cycle is halted in metaphase. Chromosomes cannot separate and affected cells cannot proliferate

Leads to apoptotic cell death

29
Q

Give an example of a Taxane

A

paclitaxel

30
Q

Give the MoA of Taxanes

A

Taxanes reversibly bind on the β tubulin subunit (at a different site to that of vinca alkaloids)

Binding stabilises the microtubules and inhibits their disassembly. This results in microtubules rendered non-functional as they cannot disassemble to pull the chromosome apart

The cell cycle remains stuck in metaphase which triggers apoptotic cell death in both cancer cells and normal cells

31
Q

Is the aim of chemotherapy the same for all cancers?

A

NO aim is very different in different malignancies

32
Q

The ‘predicted response’ of chemo differs within the same cance type, what 4 things is this based on?

A

1) performance score
2) clinical stage
3) prognostic factors or score (often involving biological factors)
4) molecular or cytogenetic markers

33
Q

What must we consider before giving chemotherapy?

A

Side effects vs anticipated or best outcome

34
Q

What are the 2 broad chemotherapy regimens?

Which is more commonly given and why?

A

1) a single drug
2) combination chemotherapy (number of different drugs)

Combination is more common because it reduces the chances of cell resistance

35
Q

Give 4 routes of administration for chemotherapy

A

IV = most common

36
Q

What are the 2 types of IV pumps?

A

1) PICC Line
2) Hickman Line

37
Q

Give 4 side effects of chemotherapy

A
38
Q

What are the adverse effects of chemotherapy due to?

A

The effect of treatment on the tumour

39
Q

Give 3 adverse effects of chemotherapy (systemic effects)

(Incl why and/or type of cancer commonly involved)

A

1) Acute renal failure (multifactorial) ➞ rapid tumour lysis leads to precipitation of urate crystals in renal tubules causing hyperuricaemia
2) GI perforation at site of tumour (reported in lymphoma)
3) Disseminated intravascular coagulopathy: eg. onset within a few hours of starting treatment for acute myeloid leukaemia

40
Q

Why does chemotherapy cause vomiting?

Give the 3 patterns of emesis seen

A

Due to direct action of chemotherapy drugs on the central chemoreceptor trigger zone (+ multifactorial)

Patterns of emesis

  • acute phase 4 - 12 hours
  • delayed onset, 2 - 5 days later
  • chronic phase, may persist up to 14 days
41
Q

When does Alopecia tend to occur during chemo and how may this vary during treatment course?

A

Hair thins at 2 - 3 weeks

May be total but may re-grow during therapy (difficult to predict)

….Help sometimes with scalp cooling

42
Q

Give 3 chemo drugs associated with alopecia and one drug that is less so

A

Marked with doxorubicin, vinca alkaloids and cyclophosphamide

Minimal with platinums

43
Q

Give 2 local skin toxicity effects of chemo

A

1) Irritation and thrombophlebitis of veins
2) Extravasation

44
Q

What are the general skin toxicity effects associated with Bleomycin

A

Hyperkeratosis, hyperpigmentation, ulcerated pressure sores

45
Q

Give 2 drugs associated with hyperpigmentation

(general skin toxicity effects)

A
  1. Busulphan
  2. Doxorubicin
  3. Cyclophosphamide
  4. Actinomycin D
46
Q

Why may mucositis occur with chemo and in which part of the GIT is it usually worst?

Give 3 presenting symptoms of this

A

Due to GIT epithelial damage. It may be profound and involve whole tract and is most commonly worst in the oropharynx

Presents as

  1. Sore mouth/throat
  2. Diarrhoea
  3. G.I. bleed
47
Q

Give 2 chemo drugs associated with cardio-myopathies

A

1) Doxorubicin ++ (> 550 mg/m2)
2) High dose cyclophosphamide

48
Q

Give 2 chemo drugs associated with Arrhythmias

A

1) Cyclophosphamide
2) Etoposide

49
Q

Give 2 chemo drugs associated with pulmonary fibrosis (lung toxicity)

A
  1. Bleomycin
  2. Mitomycin C
  3. Cyclophosphamide
  4. Melphalan
  5. Chlorambucil
50
Q

What is the most common dose limiting toxicity and most frequent cause of death from toxicity

A

Haematological Toxicity - different agents cause variable effects on degree and lineages ie. neutrophils and platelets

It is these effects of leukopenia etc that make it ‘dose limiting’

51
Q

State the following for chemotherapy drugs:

  • theraputic window
  • side effects
  • inter-subject variability
  • treatment regimes
A

narrow theraputic window

significant side effects

high inter-subject variability ➞ dose needs to be altered for the individual patient

balanced treatment regimes required

52
Q

Give 3 individual patient factors that influence dose of chemotherapy

A

1) their surface area and/or body mass index
2) drug handling ability (eg. liver function, renal function…dependent on metabolism and excretion routes)
3) general wellbeing (performance status and comorbidity)

53
Q

Treatment phasing needs to take into account balance between what 4 things?

A

1) growth fraction
2) the ‘cell kill’ of each cycle of the chemotherapy regimen
3) marrow and GI tract recovery before next cycle
4) how tolerable is the regimen (short term organ toxicity, physical side effects and long term damage causing late effects)

54
Q

Give 4 PK factors that cause variability for chemo treatment + examples

A

Abnormalities in:

1) absorption: N+V, compliance, gut problems
2) distribution: Weight loss, reduced body fat, ascites
3) elimination: liver/renal dysfunction, other meds
4) protein binding: low albumin, other drugs

55
Q

Give 4 drugs which may increase plasma levels of the chemotherapy drug (and therefore side effects)

Drug-drug interactions

A

1) Vincristine + itraconazole (antifungal) leads to more neuropathy
2) Capecitabine (oral 5FU) + warfarin
3) Methotrexate + penicillin or NSAIDs
4) Capecitabine + St Johns Wort and grapefruit juice

56
Q

Give 3 ways we can monitor the response of cancer to the treatment

A

1) Radiological imaging
2) Tumour marker blood tests
3) Bone marrow/cytogenetics

57
Q

How can we monitor drug levels of Methotrexate during treatment?

A

Methotrexate drug assays taken on serial days to ensure clearance from the blood after folinic acid rescue

58
Q

Give 2 ways we can monitor organ damage during chemo treatment

A

1) Creatinine clearance
2) Echocardiogram

59
Q

Clinical Trials: how do the drugs get from bench to bedside?

A
60
Q

What is ‘targeted drug therapy’ + examples

A

Using molecular biology to identify targets in:

  • monoclonal antibodies
  • cytokines
  • inhibiting angiogenesis
  • targeting gene expression
  • signal transduction inhibitors
  • interfering with the apoptotic pathways
  • interfering with cell cycle control
61
Q

Define a neoadjuvant vs an adjuvant

A

Neoadjuvant - given before surgery or radiotherapy for the primary cancer

Adjuvant - given after surgery to excise the primary cancer, aiming to reduce relapse risk eg breast cancer

62
Q

Define the following:

  • Palliative
  • Primary
  • Salvage
A

Palliative - to treat current or anticipated symptoms without curative intent

Primary – 1st line treatment of cancer.. In many haematological cancers this will be with curative intent, initially aiming for remissiom

Salvage – chemotherapy for relapsed disease

Pharmacology (Semester 6) (17 decks)

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