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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
What are the main alkylating agents?
Platinum compounds
26
How do platinum compounds work in chemo?
Form platinated inter- and intra- strand adducts
27
What % of adducts are G-G?
55%
28
What % of adducts are G-A?
31%
29
What is more effective than platinum adducts and why?
DACH platinum adducts - bulkier
30
How do spindle poisons work?
bind to microtubules to disrupt the mechanics to inhibit and stimulate polymerisation and prevent depolymerisation (weird eh?)
31
Name 3 mechanisms of resistance?
-Decreased entry/Increased exit of agent form cell-Inactivation of agent within cell-Enhanced repair of DNA lesions produced by alkylation
32
How can chemo be administered?
The usual - IV, PO, SC, topically, into body cavity, intralesionally, intrathecally, and rarely IM.
33
What is the most common route of administration?
IV
34
How is IV chemo administered?
Bolus and infusional bag, or continuous pump infusion
35
Why do side effects occur?
Chemo works on all cells that are rapidly dividing
36
What else can cause side effects (other than the chemo directly)?
The toxins etc released by the tumour cell due to treatment on it
37
What side effect can these toxins have on the kidneys?
Acute renal failure due to urate crystals in the tubules (toxins -> hyperuricaemia)
38
What side effect can these toxins have on the CVS?
Disseminated intravascular coagulopathy
39
What can happen at the site of a tumour?
Perforation eg in the GI tract for lymphoma
40
What is the main cause of vomitting due to chemo?
Action of the chemo on the central chemoreceptors trigger zone
41
What patterns of emesis can occur?
-Acute phase (4-12 hrs)-Delayed onset (2-5 days later)-Chronic phase (may persist up to 14 days)-Anticipatory
42
When does alopecia occur?
2-3 weeks into chemo
43
Which chemo drugs are especially associated with alopecia?
-Doxorubicin-Vinca alkaloids-Cyclophosphamide
44
Which chemo drugs is alopecia minimal with?
Platinums
45
How can skin toxicity occur?
Locally or generally
46
Describe local skin toxicity
Irritation and thrombophlebitis of veins at site of IV insertion. Extravasation can occur.
47
Which chemo agents can cause general skin toxicity?
-Bleomycin-Busulphan-Doxorubicin-Cyclophosphamide
48
When can generalised skin toxicity occur especially?
When chemo is given orally/as a tablet taken at home. Over compliance.
49
What is the most frequent cause of death by toxicity with chemo?
Haematological toxicity
50
What is the therapeutic window for chemo?
Narrow
51
Why is specialist precribing needed?
Narrow therapeutic indices and significant side effect profile
52
What needs to be taken into account when altering dose?
-BMI-Body SA-Drug handling ability (renal/hepatic function)-General wellbeing
53
What causes variability in pharmacokinetics?
Variations in ADME and protein binding
54
What can alter absorption?
-N&V-Compliance-Gut problems
55
What can alter distribution?
-Weight loss-Body fat-Ascites
56
What can alter elimination?
-Liver/renal function-Other medications
57
What can alter protein binding?
-Low albumin-Displacemnt by other drugs
58
Which drug interaction increases neuropathy side effects?
Vincristine and Itraconazole (common antifungal)
59
Which chemo agent does warfarin interact with?
Capecitabine (oral 5FU)
60
What must be taken into account when prescribing methotrexate?
-Penicillin-NSAIDs
61
What chemo agent do St John's Wart and grapefruit/cranberry juice interact with?
Capecitabine/Oral 5-FU
62
What 3 things should be monitored during treatment?
-Response of cancer-Drug levels-Organ damage
63
Where does carcinoma spread to especially?
Lungs
64
How does carcinoma spread mainly/early?
Via lymphatics
65
Where do sarcomas often spread?
To liver
66
How do sarcomas often spread?
Via the blood
67
When is radical chemotherapy treatment used?
Rarely, for haematological malignancies (not solid tumours)
68
What do intercalating agents target?
DNA transcription and duplication
69
How does topoisomerase work?
Recognises supercoiled DNA, and allows it to uncoil by cutting and rejoining it. Transient single-strand cleavage
70
What can we do to topoisomerase?
Inhibit it
71
What inhibits topoisomerase 1?
CPT-11
72
How does CPT-11 inhibit topoisomerase?
Binds to the complex with DNA without affecting the cleavage reaction
73
How does CPT-11 cause double strand break?
Causes the topoisomerase to bind to the DNA in such a way that the strands cannot join back together.
74
What agent can minimise side effects in theory?
Unique tumour-activated agents
75
Name a unique tumour-activated agent
Xel oda
76
How does xel oda work in theory?
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
What is TP enzyme?
Thymidine phosphorylase
78
What actually happens with unique tumour-activated agents?
There are lots of side effects, but they are different to those assocuated with chemo normally
79
What is the aim of combination therapy?
To increase efficacy while keeping activity and safety in a balance.
80
How is safety measured in combination therapy?
Compatability of side effects i.e. dont give a pt 2 drugs with bone toxicity, should have different side effect profile
81
What is considered when choosing combination therapy with respect to activity?
Choosing drugs with different mechanisms of action and resistance
82
How is a drug pumped out of the tumour cell?
Via P-glycoprotein
83
What is the P-glycoprotein?
An ATP-powered efflux pump
84
What does P-glycoprotein do?
Pumps cytotoxic agents out of the cell against the concentration gradient
85
What mechanism of DNA repair has importance in bowel cancer?
Mismatch repair
86
What enzyme takes part in base excision repair?
PARP
87
What type of strand break is base excision repair for?
Single
88
What type of strand break is recombinational repair for?
Double
89
What enzymes take part in recombinational repair?
ATM and DNA-PK
90
What enzymes take part in mismatch repair?
MSH2 and MLH1
91
How does PARP work?
Binds directly to single strand breaks, then modifies itself to produce large branched chains of PAR. Repair enzymes are recruited to this complex
92
How are PAR chains degraded?
By PARG
93
What does PARP inhibition do?
Increases double-strand DNA damage
94
How does PARP inhibition cause DNA DSB?
It prevents the recruitment of repair factors, so SSB becomes a DSB in next replication attempt
95
What is olaparib?
A PARP inhibitor
96
What is PARP inhibition used to treat?
Tumours with BRCA1 nd BRCA2 mutations
97
What happens due to PARP inhibition in a BRCA-deficient cell?
SSB -> DSB -> No repair as deficient HR pathway -> cancer cell death
98
Give example of hormones that can be carcinogenic
-Oestrogen-Testosterone
99
What is important in hormones causing cancer?
Prolonged exposure eg age of menarche, age of first pregnancy etc
100
Name an antioestrogen
Tamoxifen
101
Name a synthetic progestogen
Megestrol
102
Name an LHRH agonist
Goserelin
103
What is goserelin used for?
Rendering women who are pre-menopausal post-menopausal
104
What endocrine inhibitors can be used in breast cancer therapy?
Aromatase inhibitors
105
Name some aromatase inhibitors?
-Anastrozole-Letrozole-Exemestane-Vorozole-Formestane
106
Which women are aromatase inhibitors used in?
Post-menopausal
107
Why can't aromatase inibitors be used in pre-menopausal women?
After menopause, aromastase is relied on to produce oestrogen, but not before menopause
108
What classes of endocrine therapies are there for prostate cancer currently?
-LHRH agonists-Antiandrogens-Oestrogen-Castration
109
Name some antiandrogens
-Cyproterone acetate-Flutamide-Bicalutamide
110
What is a novel agent used in prostate cancer?
Abiraterone
111
How does Abiraterone work?
Inhibits CYP 17A1
112
What is CYP 17A1 crucial for?
Conversion of pregnenolone and progesterone to testosterone

Clinical Pharmacology and Therapeutics (26 decks)

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