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Clinical Pharmacology and Therapeutics > Biological Basis of Chemotherapy > Flashcards

Biological Basis of Chemotherapy Flashcards

1
Q

What was the first chemo agent?

A

Mustard gas

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2
Q

What was nitrogen mustard used to treat?

A

Lymphoma

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3
Q

How has nitrogen mustard improved survival?

A

Increased survival of children with acute lymphoblastic leukaemia over past 5 decades.

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4
Q

How are most chemo agents discovered?

A

Serendipity

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5
Q

What is the active ingredient in Cisplatin?

A

Platinum complex

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6
Q

What is the NCI?

A

The National Cancer Institue

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7
Q

What do the NCI do?

A

Screen plant and marine organic material for anti-cancer activity

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8
Q

What is an example of a compound found by the NCI?

A

Trabectedin

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9
Q

What is trabectedin liscenced in?

A

Sarcoma

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10
Q

Which part of the cell cycle varies in time the most?

A

G1

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11
Q

How long can G1 take?

A

0-30 hours

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12
Q

Are all cells within the cell cycle all the time?

A

No

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13
Q

What is the problem with cancer cells in G0?

A

They cannot be targetted in cancer treatment

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14
Q

How is this problem of G0 solved?

A

Agents developed that push cancer cells into the cell cycle

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15
Q

What is the fractional cell kill hypothesis?

A

Timing of chemo doses is important - if given in fractionated doses, the normal tissue recovers better than cancer tissue between doses so the effect on normal tissue is minimalised.

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16
Q

Name some tumours that are highly chemosensitive

A

-Lymphomas-Germ cell tumours-Small Cell Lung -Neuroblastoma-Wilm’s Tumour (paediatric kidney cancer)

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17
Q

Name some tumours that are modestly chemosensitive

A

-Breast-Colorectal-Bladder-Ovarian-Cervical

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18
Q

Name some tumours that have low chemosensitivity

A

-Prostate-Renal cell-Brain tumours-Endometrial

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19
Q

What are the 4 categories of cytotoxic agent?

A

-Antimetabolites-Alkylating Agents-Spindle Poisons-Intercalating Agents

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20
Q

How do antimetabolites work?

A

Act to inhibit synthesis of molecules needed for DNA replication/synthesis usually by enzyme inhibition

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21
Q

Give some examples of anti-metabolites

A

-5-Fluorouracil-Methotrexate

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22
Q

How does 5-fluorouracil work?

A

Metabolised to 5-FdUMP which inhibits thymidylate synthase = precursor convertor

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23
Q

How does methatrexate work?

A

Inhibits dihydrofolate reductase in folate cycle so purine/amino acid synthesis inhibited.

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24
Q

How do alkylating agents work?

A

Join DNA strands together to inhibit replication

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25
Q

What are the main alkylating agents?

A

Platinum compounds

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26
Q

How do platinum compounds work in chemo?

A

Form platinated inter- and intra- strand adducts

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27
Q

What % of adducts are G-G?

A

55%

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28
Q

What % of adducts are G-A?

A

31%

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29
Q

What is more effective than platinum adducts and why?

A

DACH platinum adducts - bulkier

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30
Q

How do spindle poisons work?

A

bind to microtubules to disrupt the mechanics to inhibit and stimulate polymerisation and prevent depolymerisation (weird eh?)

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31
Q

Name 3 mechanisms of resistance?

A

-Decreased entry/Increased exit of agent form cell-Inactivation of agent within cell-Enhanced repair of DNA lesions produced by alkylation

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32
Q

How can chemo be administered?

A

The usual - IV, PO, SC, topically, into body cavity, intralesionally, intrathecally, and rarely IM.

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33
Q

What is the most common route of administration?

A

IV

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34
Q

How is IV chemo administered?

A

Bolus and infusional bag, or continuous pump infusion

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35
Q

Why do side effects occur?

A

Chemo works on all cells that are rapidly dividing

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36
Q

What else can cause side effects (other than the chemo directly)?

A

The toxins etc released by the tumour cell due to treatment on it

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37
Q

What side effect can these toxins have on the kidneys?

A

Acute renal failure due to urate crystals in the tubules (toxins -> hyperuricaemia)

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38
Q

What side effect can these toxins have on the CVS?

A

Disseminated intravascular coagulopathy

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39
Q

What can happen at the site of a tumour?

A

Perforation eg in the GI tract for lymphoma

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40
Q

What is the main cause of vomitting due to chemo?

A

Action of the chemo on the central chemoreceptors trigger zone

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41
Q

What patterns of emesis can occur?

A

-Acute phase (4-12 hrs)-Delayed onset (2-5 days later)-Chronic phase (may persist up to 14 days)-Anticipatory

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42
Q

When does alopecia occur?

A

2-3 weeks into chemo

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43
Q

Which chemo drugs are especially associated with alopecia?

A

-Doxorubicin-Vinca alkaloids-Cyclophosphamide

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44
Q

Which chemo drugs is alopecia minimal with?

A

Platinums

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45
Q

How can skin toxicity occur?

A

Locally or generally

46
Q

Describe local skin toxicity

A

Irritation and thrombophlebitis of veins at site of IV insertion. Extravasation can occur.

47
Q

Which chemo agents can cause general skin toxicity?

A

-Bleomycin-Busulphan-Doxorubicin-Cyclophosphamide

48
Q

When can generalised skin toxicity occur especially?

A

When chemo is given orally/as a tablet taken at home. Over compliance.

49
Q

What is the most frequent cause of death by toxicity with chemo?

A

Haematological toxicity

50
Q

What is the therapeutic window for chemo?

A

Narrow

51
Q

Why is specialist precribing needed?

A

Narrow therapeutic indices and significant side effect profile

52
Q

What needs to be taken into account when altering dose?

A

-BMI-Body SA-Drug handling ability (renal/hepatic function)-General wellbeing

53
Q

What causes variability in pharmacokinetics?

A

Variations in ADME and protein binding

54
Q

What can alter absorption?

A

-N&V-Compliance-Gut problems

55
Q

What can alter distribution?

A

-Weight loss-Body fat-Ascites

56
Q

What can alter elimination?

A

-Liver/renal function-Other medications

57
Q

What can alter protein binding?

A

-Low albumin-Displacemnt by other drugs

58
Q

Which drug interaction increases neuropathy side effects?

A

Vincristine and Itraconazole (common antifungal)

59
Q

Which chemo agent does warfarin interact with?

A

Capecitabine (oral 5FU)

60
Q

What must be taken into account when prescribing methotrexate?

A

-Penicillin-NSAIDs

61
Q

What chemo agent do St John’s Wart and grapefruit/cranberry juice interact with?

A

Capecitabine/Oral 5-FU

62
Q

What 3 things should be monitored during treatment?

A

-Response of cancer-Drug levels-Organ damage

63
Q

Where does carcinoma spread to especially?

A

Lungs

64
Q

How does carcinoma spread mainly/early?

A

Via lymphatics

65
Q

Where do sarcomas often spread?

A

To liver

66
Q

How do sarcomas often spread?

A

Via the blood

67
Q

When is radical chemotherapy treatment used?

A

Rarely, for haematological malignancies (not solid tumours)

68
Q

What do intercalating agents target?

A

DNA transcription and duplication

69
Q

How does topoisomerase work?

A

Recognises supercoiled DNA, and allows it to uncoil by cutting and rejoining it. Transient single-strand cleavage

70
Q

What can we do to topoisomerase?

A

Inhibit it

71
Q

What inhibits topoisomerase 1?

A

CPT-11

72
Q

How does CPT-11 inhibit topoisomerase?

A

Binds to the complex with DNA without affecting the cleavage reaction

73
Q

How does CPT-11 cause double strand break?

A

Causes the topoisomerase to bind to the DNA in such a way that the strands cannot join back together.

74
Q

What agent can minimise side effects in theory?

A

Unique tumour-activated agents

75
Q

Name a unique tumour-activated agent

A

Xel oda

76
Q

How does xel oda work in theory?

A

Absorbed in GI tract, Liver converts it to 5’-DFCR (inactive) and 5’-DFUR (active). These both move into tumour tissue over healthy tissue and convert to 5-FU via TP enzyme

77
Q

What is TP enzyme?

A

Thymidine phosphorylase

78
Q

What actually happens with unique tumour-activated agents?

A

There are lots of side effects, but they are different to those assocuated with chemo normally

79
Q

What is the aim of combination therapy?

A

To increase efficacy while keeping activity and safety in a balance.

80
Q

How is safety measured in combination therapy?

A

Compatability of side effects i.e. dont give a pt 2 drugs with bone toxicity, should have different side effect profile

81
Q

What is considered when choosing combination therapy with respect to activity?

A

Choosing drugs with different mechanisms of action and resistance

82
Q

How is a drug pumped out of the tumour cell?

A

Via P-glycoprotein

83
Q

What is the P-glycoprotein?

A

An ATP-powered efflux pump

84
Q

What does P-glycoprotein do?

A

Pumps cytotoxic agents out of the cell against the concentration gradient

85
Q

What mechanism of DNA repair has importance in bowel cancer?

A

Mismatch repair

86
Q

What enzyme takes part in base excision repair?

A

PARP

87
Q

What type of strand break is base excision repair for?

A

Single

88
Q

What type of strand break is recombinational repair for?

A

Double

89
Q

What enzymes take part in recombinational repair?

A

ATM and DNA-PK

90
Q

What enzymes take part in mismatch repair?

A

MSH2 and MLH1

91
Q

How does PARP work?

A

Binds directly to single strand breaks, then modifies itself to produce large branched chains of PAR. Repair enzymes are recruited to this complex

92
Q

How are PAR chains degraded?

A

By PARG

93
Q

What does PARP inhibition do?

A

Increases double-strand DNA damage

94
Q

How does PARP inhibition cause DNA DSB?

A

It prevents the recruitment of repair factors, so SSB becomes a DSB in next replication attempt

95
Q

What is olaparib?

A

A PARP inhibitor

96
Q

What is PARP inhibition used to treat?

A

Tumours with BRCA1 nd BRCA2 mutations

97
Q

What happens due to PARP inhibition in a BRCA-deficient cell?

A

SSB -> DSB -> No repair as deficient HR pathway -> cancer cell death

98
Q

Give example of hormones that can be carcinogenic

A

-Oestrogen-Testosterone

99
Q

What is important in hormones causing cancer?

A

Prolonged exposure eg age of menarche, age of first pregnancy etc

100
Q

Name an antioestrogen

A

Tamoxifen

101
Q

Name a synthetic progestogen

A

Megestrol

102
Q

Name an LHRH agonist

A

Goserelin

103
Q

What is goserelin used for?

A

Rendering women who are pre-menopausal post-menopausal

104
Q

What endocrine inhibitors can be used in breast cancer therapy?

A

Aromatase inhibitors

105
Q

Name some aromatase inhibitors?

A

-Anastrozole-Letrozole-Exemestane-Vorozole-Formestane

106
Q

Which women are aromatase inhibitors used in?

A

Post-menopausal

107
Q

Why can’t aromatase inibitors be used in pre-menopausal women?

A

After menopause, aromastase is relied on to produce oestrogen, but not before menopause

108
Q

What classes of endocrine therapies are there for prostate cancer currently?

A

-LHRH agonists-Antiandrogens-Oestrogen-Castration

109
Q

Name some antiandrogens

A

-Cyproterone acetate-Flutamide-Bicalutamide

110
Q

What is a novel agent used in prostate cancer?

A

Abiraterone

111
Q

How does Abiraterone work?

A

Inhibits CYP 17A1

112
Q

What is CYP 17A1 crucial for?

A

Conversion of pregnenolone and progesterone to testosterone

Clinical Pharmacology and Therapeutics (26 decks)

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