Anti Cancer Drugs

Question 1

Where did anti-cancer drugs start?

Answer 1

WWI mustard gas had physicians exploring why it was so toxic

Question 2

What is Adjuvant Chemotherapy?

Answer 2

reduction in the risk of recurrence (mop up Micrometastases) given after tumour surgery.

Question 3

What is Neo-adjuvant chemotherapy?

Answer 3

Facilitation of local resection and impact of micrometastatic disease prior to tumour treatment surgery.

Question 4

What does palliative mean?

Answer 4

Improve the quality and quantity of life in the advanced disease setting

(curative is when someone is cured)

Question 5

What are the different types of drugs used to combat cancer?

Answer 5

Cell cycle specific drugs

Cell cycle non-specific drugs

Question 6

What are cell cycle specific drugs?

Answer 6

inhibit cell growth at specific phases

Question 7

What are cell cycle non-specific drugs?

Answer 7

act on all cells independent of whether they are cycling or not

Question 8

What type of agent is mustard gas?

Answer 8

Alkylating agent

Question 9

What are alkylating agents?

Answer 9

Covalently transfer alkyl groups to DNA bases

Question 10

How do alkylating agents work?

Answer 10

Alkylation of two bases results in cross bridges
cross linking prevents DNA from being separated for DNA synthesis or transcription.
not cell cycle specific as it binds to all DNA

Question 11

What are the pharmacological actions of alkylating agents?

Answer 11

Cytotoxic actions:
interfere with DNA integrity and functions to induce cell death in rapidly proliferating tissues

Lethality of DNA alkylation depends on the recognition of the adduct

in nondividing cells, DNA damage activation depends on the presence of p53 gene.

malignant cells with mutant/absent p53 gene fail to suspend cell cycle progression

Question 12

What do platinum agents do?

Answer 12

Bind covalently to purine DNA bases
Bifunctional intra strand cross links
Preventing DNA double strands from separating
Not S-phase specific
Binding of cisplatin to DNA is irreversible and structurally different adducts are formed.
The adducts are classified as intra-strand crosslinking of two nucleobases of single DNA strand, inter-strand crosslinking of two different strands of one DNA molecule, chelate formation through N- and O-atoms of one guanine, and DNA-protein crosslinks
Very similar to the alkylating agents

Question 13

What are anti metabolites?

Answer 13

purine/pyrimidine analogues

Question 14

How do anti metabolites work?

Answer 14

Act at the level of synthesis

interfere with incorporation of nucleic acids

Usually S phase specific

Question 15

What are some pyrimidine antimetabolites?

Answer 15

5FU and capecitabine

Question 16

Give an example of anti-folates?

Answer 16

methotraxate

Question 17

What are the problems with anti metabolites?

Answer 17

Acts on both normal and cancer cells that are actively dividing and thus causes significant side effects e.g bone marrow and gastrointestinal toxicity

Question 18

What is 5FU?

Answer 18

5-fluorouracil

thymidine analogue

binds to thymidylate and as a result the enzyme is inhibited and leads to reduced DNA synthesis and decreased cell proliferation

Question 19

What is methotrexate?

Answer 19

Competitively inhibits dihydrofolate reductase

inhibits the enzymes activity for DNA synthesis and thus leads to less.

Question 20

What are topoisomerase inhibitors?

Answer 20

Topo1 - single strand breaks

Topo2 - double strand breaks

Question 21

What do topoisomerases do?

Answer 21

Relax supercoiled dsDNA allowing replication and RNA transcription

Question 22

What do topoisomerase inhibitors do?

Answer 22

Topo1:
Bind to and stabilise the DNA-topoisomerase 1 adducts
Inhibits re-ligation of DNA strands and thus results in Single strand breaks in DNA which then likely mediate apoptosis
E.g Irinotecan and camptothecin

Topo2:
Forms a complex with topo2 after cleavage of DNA
Inhibits re-ligation and leaves single and double strand breaks
E. g etoposide and anthracyclines

Question 23

What do Anthracyclines do?

Answer 23

Topoisomerase II inhibition
DNA intercalation ss and ds DNA breaks
Free radical formation binding to DNA

Question 24

What is the toxicity of anthracyclines?

Answer 24

myelosuppression
gastrointestinal
alopecia
local tissue damage
cardiotoxicity

Question 25

What are the two types of microtubule inhibitors?

Answer 25

Vinca Alkaloids

Taxanes

Question 26

What do Vinca Alkaloids do?

Answer 26

stops assembly and promotes disassembly (high affinity binding to ends)
splaying and spiralling (low affinity binding to sides)
metaphase arrest, plus other cell cycle functions
toxicity - neuro, GI, marrow

Question 27

What do Taxanes do?

Answer 27

stabilise microtubules, inhibit dynamic reorganisation
sustained metaphase / anaphase block
toxicity - neuro, marrow

Question 28

What are the areas with reversible toxicities of anti-cancer drugs?

Answer 28

Affect rapidly dividing cells

bone marrow

GIT

Germinal epithelium

lymphoid tissue

hair follicales

Question 29

What are the areas where they are irreversible toxicities?

Answer 29

Kidney
Nerves
Heart
Lungs

Question 30

What are the assumptions of cytotoxic Chemotherapy?

Answer 30

Tumour growth proceeds exponentially, independent of growth homeostasis, but:
some are non-dividing cells
growth fraction may vary as a function of the tumour size

Each dose results in the same proportional log kill, but:
Proportional kill
tumours are heterogeneous

Intensity of dose influences outcome:
Cytotoxic drugs are given at close to the maximum tolerated dose

Different drugs have different kill properties

Question 31

What are the aims of combination chemotherapy?

Answer 31

Achieve maximum cell kill with tolerable toxicity

increase kill fraction of resistant cells

prevent or slow outgrowth of resistant malignant tumours

Question 32

What type of anti-cancer drug regime is most beneficial?

Answer 32

Sequential regimes out perform alternative regimes.

Question 33

How can we personalise anti cancer medicine to patients?

Answer 33

Currently via randomised control trials to find a combination of drugs superior to the current ones being used.

Cannot though determine the likeliness of response in individuals