Principles of Chemotherapy I

Question 1

Targets of Drugs (4)

Answer 1

• receptors
• enzymes
• ion channels
• transporters

Question 2

Function of Chemotherapeutic drugs

Answer 2

kill or suppress the proliferation of target cells

Question 3

Principle of selective toxicity

Answer 3

drugs should be toxic to the infectious organism or tumour but not healthy host cells

Question 4

How do cancer cells differ from normal host cells? (5)

Answer 4

• uncontrolled proliferation
• de-differentiation
• loss of function
• invasion
• metastasis

Question 5

Target: Chemotherapeutic Drugs… (5)

Answer 5

1) target Proliferation
2) modify DNA structure
3) inhibit DNA synthesis
4) inhibit Mitosis
5) inhibit Inflammation

Question 6

Most chemotherapeutic agents…

Answer 6

Target Proliferation

Question 7

Drugs that modify DNA structure (4)

Answer 7

• alkylating agents
• platinum compounds
• cytotoxic agents
• topoisomerase inhibitors

Question 8

Example of Alkylating agent

Answer 8

cycle-phosphamide

Question 9

What are Alkylating agents activated by?

Answer 9

liver CYP450 mixed-function oxidases

Question 10

What do Alkylating agents alkylate? (3)

Answer 10

• DNA bases
• particularly Guanine
• at postion N7

Question 11

What do Alkylating agents do? (4)

Answer 11

• cause intra-strand or inner-strand cross linking
• interfere with both replication and translation of DNA
• disrupt DNA synthesis in S-phase
• causes cell cycle arrest and apoptosis at G2 checkpoint

Question 12

Example of a Platinum compound

Answer 12

Cisplastin

Question 13

What do Platinum compounds do? (4)

Answer 13

• form a reactive complex in cell which binds to N7 and O6 at guanine
• cause intra-strand cross linking
• disrupt DNA synthesis (S-phase)
• cause cell cycle arrest and apoptosis (G2 checkpoint)

Question 14

Examples of Cytotoxic compounds (3)

Answer 14

• Bleomycin
• Anthracyclins
• Dactinomycins

Question 15

What do Cytotoxic compounds bind to? (2)

Answer 15

• DNA
• chelate Fe2+

Question 16

What do Cytotoxic compounds do? (5)

Answer 16

• lead to local production of free radicals, that break DNA strands
• intercalate between adjacent DNA bases
• inhibit Topoisomerase II
• prevent DNA replication and transcription
• causing cell cycle arrest and apoptosis (G1/2 checkpoints)

Question 17

Examples of Topoisomerase inhibitors? (2)

Answer 17

• Camptothecins
• Epipdophyllotoxins

Question 18

Topoisomerase inhibitor:

Example of Camptothecin

Answer 18

Toptecan

Question 19

Topoisomerase inhibitor:

What do Camptothecins do? (3)

Answer 19

• inhibit Topoisomerase I
• stabilise nicked single strands and prevent re-sealing
• causing cell cycle arrest and apoptosis (G2 checkpoint)

Question 20

Topoisomerase inhibitor:

Example of Epipdophyllotoxin

Answer 20

Etoposide

Question 21

Topoisomerase inhibitor:

What do Epipdophyllotoxins do? (3)

Answer 21

• inhibit Topoisomerase II
• prevent re-sealing of double strands
• often combined with Bleomycin and Cisplastin if treating metastatic cancers

Question 22

Drugs that inhibit DNA synthesis

Answer 22

Antimetabolites

Question 23

DNA synthesis inhibitor:

Examples of Antimetabolites (3)

Answer 23

• Methotrexate
• 5-fluorouracil
• 6-mercaptopurine

Question 24

DNA synthesis inhibitor:

What do Antimetabolites inhibit? (2)

Answer 24

• inhibit nucleic acid base synthesis
• DNA synthesis

Question 25

Antimetabolites: What does Methotrexate inhibit? (3)

Answer 25

- inhibits dihydrofolate reductase, preventing folate cycling - inhibits pyrimidine synthesis - inhibits purine synthesis

Question 26

Antimetabolites: What does 5-fluorouracil inhibit? (2)

Answer 26

- inhibits thymidylate synthetase - inhibits pyrimidine synthesis

Question 27

Antimetabolites: What does 6-mercaptopurine inhibit?

Answer 27

inhibitor of IMP dehydrogenation/deamination

Question 28

Drugs that inhibit Mitosis (2)

Answer 28

- Vinca Alkaloids - Taxanes

Question 29

Mitosis inhibitor: Examples of Vinca Alkaloids (2)

Answer 29

- Vincristines - Vinblastine

Question 30

Mitosis inhibitor: What do Vinca Alkaloids do? (4)

Answer 30

- inhibit polymerisation of microtubules - inhibit formation of mitotic spindle - mitosis arrested in Metaphase - cell cycle arrested in M-phase

Question 31

Mitosis inhibitor: Example of Taxane

Answer 31

Paclitaxel

Question 32

Mitosis inhibitor: What do Taxanes do?

Answer 32

- stabilise polymerised microtubules - prevent release of chromosomes from spindle

Question 33

Drugs that inhibit Inflammation

Answer 33

Anti-inflammatory drugs

Question 34

Example of Anti-inflammatory drug

Answer 34

Dexamethasone

Question 35

Drugs that inhibit Inflammation: What does Dexamethasone do? (5)

Answer 35

- anti-inflammatory synthetic glucocorticoid - mimics action of cortisol (stress hormone) - increases expression of anti-inflammatory genes and suppresses expression of pro-inflammatory genes - prevents formation of hospitable environment/enhanced blood supply - reduces swelling around tumour

Question 36

Drugs beyond Chemotherapy

Answer 36

Depleting Growth Substrates

Question 37

Drugs beyond Chemotherapy:

Question 38

Drugs beyond Chemotherapy: Example of Depleting Growth Substrates

Answer 38

L-asparaginase

Question 39

Drugs beyond Chemotherapy: What does L-asparaginase do?

Answer 39

- breaks down L-asparagine - L-asparagine is needed in environment for cancer