Cytotoxics

Question 1

Antimetabolites - Target Enzymes Involved in Nucleotide Synthesis

Answer 1

Purine and pyrimidine analogues (inhibit key enzymes) and folate analogues (inhibit essential cofactors) both inhibits DNA replication
Work at the S phase
Methotrexate inhibts DHFR -> cannot make folate for purines
5’flurouracil (pyrimidine analogue) inhibits thymidylate synthesis

Question 2

Alkylating agents - Drugs Targeting DNA Structure and Template Activity

Answer 2

Cause the cross linkage of guanine bases-> inhibits DNA replication

Guanine N7 alkylation can form an Erol tautomer which binds to thymidine causing mismatching of bases leading to defective coding

Can also cause the cleavage of the imidazole ring causing exclusion of guanine residues leading to DNA breakage

All phases ^

Question 3

DNA intercalators - Drugs Targeting DNA Structure and Template Activity

Answer 3

dactinomycin, doxorubicin
Insert polar aromatic ring between adjoining nucleotide bases diapering alpha helix of DNA-> inhibits DNA replication
Binding is reversible and stabilised by hydrophobic interaction between opposing aromatic rings of drug and adjacent DNA bases
Late G1, early G2 and S

Question 4

topisomerase inhibitors - Drugs Targeting DNA Structure and Template Activity

Answer 4

Act by forming a stable complex of topoisomerase enzyme/DNA/inhibitor which inhibits the rennealing function of the enzyme-> propagating DNA breaks

Question 5

Mitotic Inhibitors

Answer 5

Bind to beta tubulin and interfere with mitotic spindle formation and dissolution
Vinca alkaloids prevent assembly of micro tubule to form spindle
Taxanes inhibit disassembly of spindle in the M phase

Question 6

How does Growth fraction and type of tumour affect response to cytotoxics?

Answer 6

Cells in G0 are killed once they enter the cell cycle
Cells that are terminally differentiated are unaffected by cytotoxics
Different tumours have different growth rates
Prostate/breast cancers have a low doubling rate and therefore use hormonal therapy

Question 7

How does tumour size affect response to cytotoxics?

Answer 7

Geometric resistance increases with tumour size, limiting drug and oxygen delivery to large tumours
Tumour have necrotic and hypoxia cells which act as blood supply
Shows the adaptive ability

Question 8

Factors affecting response to cytotoxics

Stage,grade,spread

Answer 8

Start localised-> invade local tissue—> Enter blood stream

Question 9

Factors affecting response to cytotoxics

Health,age, pre-existing conditions

Answer 9

Aggressive cytotoxic therapy is not suitable for all
Liver disease (metabolism, Serum binding proteins)
Anaemia and immune disorders (cytotoxic exacerbation)
Renal impairment (excretion and toxicities)

Question 10

Factors affecting response to cytotoxics

Cancer drug resistance

Answer 10

Decreased drug uptake
Increased drug removal
Decreased drug activating enzymes
Increased drug inactivating enzymes
Increased DNA repair
An alternative metabolic pathway

Question 11

Factors affecting response to cytotoxics

Combination therapy

Answer 11

Better than single due to drug resistance and dose limiting toxicity below efficacious dose
Aim for different MOA and act at different points of cycle
Aim for minimal overlapping toxicity to spare patient from dose limiting effects
Therapy cycle timings to minimise bone marrow toxicity

Question 12

Give the MOA of cyclophosphamide (An alkylating agent/Mustard gas compound)

Answer 12

More selective mustard - P=O group should decrease availability of nitrogen lone pair
“P=O deminishes the nucleophilcity of this nitrogen”

Acrolein removed by co-administration of 2-mercaptoethanesulfonate as a ‘sacrificial’ nucleophile
Wide spectrum of activity ranging from malignant lymphomas and lymphoblastic leukaemia to carcinomas of the bronchus, breast, ovary and various sarcomas

Question 13

CAR-T process

Answer 13

1. Remove blood from patient
2. Make CAR T cells in the lab
3. Grow millions of CAR T cells
4. Infuse CAR T cells into patient
5. CAR T cells bind to cancer cells and kills them

Question 14

Advantages of CAR T

Answer 14

• Outstanding and durable patient responses
• personalised one time therapy involving off site genetic engineering
• Complimented with chemo to reduce lymphocyte count

Question 15

Disadvantages of CAR T

Answer 15

• Only applicable currently to B cell lymphomas, leukaemia
• Very expensive and labour intensive
• Serious toxicities in some patients (lower incidence to many chemos )

Question 16

What is CAR T

Answer 16

What is Chimeric Antigen Receptors Cell Therapy (CAR-T)?

CAR-T is a highly complex and innovative new treatment. CAR-T is a type of immunotherapy which involves collecting and using the patients’ own immune cells to treat their condition.