Anti-Cancer Drugs

Question 1

Why is chemotherapy given?

Answer 1

• to improve the outcome of local therapy
• adjuvant (to reduce the risk of recurrence (mop up metastases)
• neo-adjuvant-to debunk tumour ahead of localised treatment-surgery or radiotherapy and remove micro-metastasis)
• palliative- to improve quality and quantity of life in the advanced disease setting

Question 2

What are the uses of chemotherapy?

Answer 2

• curative

- palliative

Question 3

What are cell cycle specific drugs used?

Answer 3

drugs that target cells in the cell cycle and inhibits cell growth at specific phases

Question 4

What are cell cycle non-specific drugs?

Answer 4

drugs that act on cells independent of whether they are cycling or not

Question 5

How do alkylating agents (mustard gas) work?

Answer 5

• covalently transfer alkyl groups to DNA bases
• mon-alkylation leads to single strand breaks
• alylation of two basses results in cross bridges
• cross-linking prevents DNA from being separated for DNA synthesis or transcription
• results in cell apoptosis

Question 6

Are alkylating agents cell cycle specific?

Answer 6

no

Question 7

What can have resistance to alkylating agents?

Answer 7

malignant cells with mutant/ absent p53 gene fail to suspend cell-cycle progression (don’t cause apoptosis) and exhibit resistance to alkylating agents

Question 8

What is the role of platinum agents?

Answer 8

• bind covalently to purine DNA bases
• bifunctional intra strand cross links
• preventing DNA strands from separating
• binding of cisplatin to DNA is irreversible and structurally different adducts are formed

Question 9

What is a disadvantage of using anti-metabolites?

Answer 9

acts on both normal and cancer cells that are dividing and this causes bad side effects

Question 10

How do topoisomerase inhibitors work?

Answer 10

-DNA topoisomerase are enzymes that relax supercoiled dsDNA allowing replication and RNA transcription
…………….

Question 11

How does 5-fluorouracil work?

Answer 11

• acts as an antimetabolite binding to thymidylate synthase
• as a result, the enzyme is inhibited and conversion of deoxyuridine to thymidine nucleotides fails, leading to reduced DNA synthesis, decrease in cell proliferation and the induction of cell death
• these effects are most evident in cells with high metabolic taxes

Question 12

How does methotrexate work?

Answer 12

• an anti-folate
• inhibits the synthesis of DNA, RNA, thymidylates and proteins
• methotrexate competitively inhibits dihydrofolate reductase (DHFR) an enzyme that participates in tetrahydrofolate synthesis
• affinity of methotrexate for DHFR is much higher than folate
• DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate important for DNA synthesis
• folic acid is needed for the de novo synthesis of the nucleoside thymidine required for DNA synthesis

Question 13

What are DNA topoisomerase enzymes?

Answer 13

-DNA topoisomerase are enzymes that relax supercoiled dsDNA allowing replication and RNA transcription

Question 14

How do microtubule inhibitors work?

Answer 14

-two types

• vinca alkaloids, stops assembly and disassembly (high affinity binding to ends), splaying and spiralling (low affinity binding to sides)
• metaphase arrest, plus other cell cycle functions
• taxanes
• stabilse microtubules, inhibit dynamic reorganisation
• sustained metaphase/ anaphase block

Question 15

What are some examples of tissues that have reversible toxicities?

Answer 15

• rapidly dividing cells
• bone marrow
• gastro-intestinal tract
• germinal epithelium
• lymphoid tissue
• hair follicles

(reversibility reflects compartment repopulation by recruitment of resting stem cells and this dictates time for recovery between treatment cycles)

Question 16

What are the assumptions made in the use of cytotoxic chemotherapy?

Answer 16

• tumour growth proceeds exponentially, independent of growth homeostasis but there are a proportion of non-dividing cells and a growth fraction may vary as a function of tumour cells
• each dose results in the same proportion log kill but proportional kill may also relate to growth function and tumours and heterogeneous and large tumours may be more likely to contain drug resistant clones
• intensity of dose influences outcome but cytotoxic drugs are given at close to the max tolerated dose and different drugs have different kill properties

Question 17

How does Topo1 work?

Answer 17

binds to and stabilises 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

Question 18

How does Topo2 work?

Answer 18

• forms a complex after cleavage of DNA

- inhibits re-ligation and leaves single and double strand breaks

Question 19

What are the aims of combination chemotherapy?

Answer 19

• to achieve maximum kill with tolerable toxicity
• to increase the kill fraction with resistant cells in a heterogeneous tumour population
• to prevent or slow the outgrowth of resistant malignant clones

Question 20

What are the principles of combination chemotherapy?

Answer 20

• only drugs shown to be partially effective-partially achieving complete responses
• avoid overlapping toxicities on single organ system
• optimal dose and schedule
• treatment-free interval should be the shortest compatible with recovery of the most sensitive normal tissue
• monitor response, performance status and toxicity
• sequential regimens outperform alternating regimens

Question 21

What types of tumours have the highest growth fraction?

Answer 21

clinically undetectable tumours