Anti-cancer chemotherapy

Question 1

What are the types of chemotherapy?

Answer 1

Curative - eliminate all cancer cells.
Adjuvant - after surgery to lower risk of cancer coming back.
Neo-adjuvant - before surgery to shrink tumour for easier removal.
Maintenance - prevent reoccurrence after remission.
Palliative - prolonging life and reducing symptoms.

Question 2

Why is the therapeutic window important in cancer chemotherapy?

Answer 2

The drugs are not very selective, and are cytotoxic, so there needs to be a good therapeutic window between the host cells and cancer cells.
When the drugs enter the blood stream, they need to remain long enough to have an effect.
Therefore they are normally administered by IV infusion.

Question 3

What is selective toxicity in chemotherapy?

Answer 3

Cancer cell selective toxicity is difficult to achieve as the host cells and cancer cells have subtle difference.
The active form of a drug at the site of cancer must be at appropriate concentration and for an adequate time.
Cytotoxic drugs affect both normal and cancer cells.

Question 4

What is therapeutic window of cancer chemotherapy?

Answer 4

The range must be between the dose response (therapeutic) and lethal dose (toxic).
The window is very small, so there are lots of side effects.

Question 5

What do most cancer cells exhibit that can be targeted in chemotherapy?

Answer 5

Abnormal growth, by self-sufficient growth signalling and insensitivity to anti-growth signals.
DNA instability.
Replication immortalisation.
Invasion and metastasis (leave organs).
Evasion of apoptosis.
Sustained angiogenesis (growth of blood vessels from tumour).

Question 6

What are cell cycle specific drugs?

Answer 6

5-flurouracil
Act on a specific phase of the cell cycle.

Question 7

What are cell cycle non-specific drugs?

Answer 7

Cyclophosphamide
Can act on almost all stages of cell cycle mainly on proliferation.
Not in G0 (resting)

Question 8

What is the relationship of dose response and cell survival in cell cycle non-specific drugs?

Answer 8

Linear relationship.
See picture.

Question 9

What is the relationship of dose response and cell survival in cell cycle specific drugs?

Answer 9

Downward curve
Have a dose cell survival relationship decreasing exponential.
See picture

Question 10

What are the general classes of chemotherapy in cancer?

Answer 10

Alkylating agents
Antimetabolites
DNA-binding agents (anthracyclines)
Topoisomerase inhibitors.
Microtubule inhibitors
Molecular targeted agents
Selective oestrogen inhibitors
Biological response modifiers

Question 11

What are alkylating agents?

Answer 11

Transfer methyl or ethyl groups to DNA - usually guanine.
Transformation of intrastrand cross-links causing:
DNA damage
DNA transcription and translation stopped
Apoptosis
DNA repair, leading to DNA fragmentation.
DNA instability

Question 12

What are examples of alkylating agents?

Answer 12

Nitrogen mustard - cyclophosphamide, melphalan, chorambucil.
Nitrosoureas - Lomustines, Carmustines.
Alkyl sulphonate - Busulfan.

Question 13

What is cyclophosphamide?

Answer 13

Inactive pro-drug, converted by oxidase enzymes in the liver to form active metabolites:
4-hydroxycyclophosphamide, aldophosphamide, then oxidised by ALDH to carboxycyclophosphamide then phosphamide mustard.

Question 14

How does cyclophosphamide work?

Answer 14

It forms covalent links with DNA, leading to cross-linking between DNA strands.
This interferes with DNA replication and transcription, ultimately preventing cancer cells dividing and growing.
Effective when cells divide rapidly.
Nonspecific cell cycle.
Used short term in combination as toxic.

Question 15

What are platinum compounds?

Answer 15

Don’t have an alkyl group, but act similarly to alkylating agents.
Form DNA-inter/intra- strand DNA protein crosslinks by their charge.
Cisplatin, carboplatin, oxaliplatin.

Question 16

What is it about cancer that antimetabolites work by?

Answer 16

Cancer cells have high synthesis and replication resource requirement.
Use natural sources of purines and pyrimidines from diet or metabolism.
Cancer cells have de novo synthesis - make things from scratch by breaking things down.
Druggable target - can accumulate toxic effect to cancer cells.

Question 17

What is the de novo synthesis by cancer cells?

Answer 17

Can act on thymine using the limiting enzymes thymidylate synthase and dihydrofolate reductase to make dTMP and DHF.
These are then used for their growth and synthesis.

Question 18

What are antimetabolites?

Answer 18

Target the limiting enzymes, where there is no alternative pathway so metabolites aren’t made.
The drugs resemble the substrates, then destruct synthesis and regulation of DNA and RNA as they can’t be made.
This then causes abnormalities in DNA so inhibits further synthesis.

Question 19

What is the reaction of cancer cells to make pyrmidines?

Answer 19

dUMP is converted to dTMP using thymidylate synthase, which is then used to make cytosine and thymine.

Question 20

What is the reaction of cancer cells to make purines?

Answer 20

THF and DHF are recycled using thymidylate synthase and dihydrofolate reductase to make guanine and adenine.

Question 21

What is the selectivity of antimetabolites?

Answer 21

Structural similar or compete with endogenous nucleic acid precursors and act on S-phase.
Partial cancer selectivity.

Question 22

What is methotrexate?

Answer 22

Targets folate metabolism.
Inhibits thymidine and purine biosynthesis.
Slow reversible competitive inhibitor of dihydrofolate reductase.
Leads to cell death.

Question 23

What is 5-fluoroucil?

Answer 23

Pro-drug that is activated by phosphorylation to form active 5-fluorodeoxyuridylate.
5-fluorodeoxyuridylate inhibits by binding to thymidylate synthase.
This interferes with thymidylate synthesis, so affects DNA replication.
It is a pyrimidine biosynthesis antimetabolite.

Question 24

What are anthracyclines?

Answer 24

Antibiotics that bind directly to DNA.
Cause intercalation - DNA strands breech
Inhibit repair of DNA, damages cell using machinery
Create Stable complexes with DNA and topo II enzymes.
Topo II is involved in repair and replication, so the complex leads to fragmentation and apoptosis.

Question 25

How else do anthracyclines work?

Answer 25

Interstrand crosslinks generates free radicals. The quinone group react with iron to form ROS, causes DNA damage and programmed cell death.

Question 26

What is Epirubicin?

Answer 26

Intercalates adjacent base pairs in DNA. Inhibits DNA repair, leading to fragmentation of DNA. DNA cleavage by topoisomerase II leads to cell death.

Question 27

What are topoisomerases?

Answer 27

Ubiquitous and essential to prevent and resolve DNA and RNA supercoiling during transcription and replication. Act at replication forks.

Question 28

What are the types of topoisomerases?

Answer 28

Topoisomerase I causes single cut in the single strand and then relegate the strand. Inhibited by irinotecan and topotecan. Topoisomerase II cuts both strands and then relegate. Inhibited by etoposide.

Question 29

What is etoposide?

Answer 29

Acts on S and G2 phase. Stabilises the DNA topo II. Used in sarcoma, lung, testicular cancer.

Question 30

What are microtubule inhibitors?

Answer 30

Chromatid separation during mitosis is performed by microtubules. Inhibitors are Cell cycle specific, mainly in M phase. Types of inhibitor are vinca alkaloids and taxanes.

Question 31

What are vinca alkaloids?

Answer 31

Anti-mitotic and anti-microtubule. Interact with B-tubulins, to prevent the assembly of microtubules. Vincristine is used in breast cancer, lymphomas, leukaemia. Vinblastine is used in testicular and Hodgkins.

Question 32

What are taxanes?

Answer 32

Prevent microtubule disassembly. Bind to B-subunit of tubulin and antagonises depolymerisation of microtubules. Halts mitosis. Cells have blocked G2/M phase and driven to apoptosis. e.g. paclitaxel and docetaxel.

Question 33

How does cell division begin?

Answer 33

Extracellular signalling such as growth factor to initiate cell division and growth. Receptor tyrosine kinase bind to ATP and transfers phosphates to tyrosine residues - leading to docking sites downstream signalling proteins.

Question 34

What are small molecule inhibitors?

Answer 34

They compete for the ATP binding site kinases. BCR-ABL: imatinib HER-2: lapatinib VEGFR: sunitinib EGFR: erlotinib

Question 35

What are tyrosine kinase inhibitors?

Answer 35

Tyrosine kinase is often mutated in cancers. Can be inhibited by imatinib mesylate, which binds ATP binding site and stabilises the inactive form of the kinase. Used in Philadelphia CML and GIT tumours.

Question 36

What are monoclonal antibodies?

Answer 36

Either target the extracellular end of the GFR or target chemotherapy to target cells. Normally used in combination with paclitaxel. There is individualised treatment based on the expression profile of the tumour. They are very good at targeting specific proteins.

Question 37

What are examples of monoclonal antibodies?

Answer 37

HER-2 receptor which is overexpressed in breast cancer, is treated with trastuzumab which interacts with the receptor to affect its function. Cetuximab targets EGFR, overexpressed in colon cancer. Non-Hodgkin's lymphoma and CLL B cells overexpress CD20, targeted by rituximab.

Question 38

What are selective oestrogen receptor modulators?

Answer 38

SERM are distinct from oestrogen, but interact with the receptors. Modulators include Tamoxifen, anastrozole, down regulators.

Question 39

What is tamoxifen?

Answer 39

SERM that competes with oestrogen for the receptor site. Used in oestrogen receptor positive breast cancer, and prophylaxis in HR patients.

Question 40

What is anastrozole?

Answer 40

Aromatase inhibitor, competitive inhibitor of aromatase enzyme, blocks the synthesis of oestrogen by binding to the oestrogen receptor.

Question 41

What are down regulators?

Answer 41

Selective oestrogen receptor down regulators, the antagonist interferes with the binding of oestradiol to oestrogen receptors, induces rapidly down regulation of ER. Block endocrine dependent independent ER signalling in ER breast cancer.

Question 42

What are biological response modifiers?

Answer 42

Influence biological response that uses substances made from living organisms to treat disease. Either naturally in body or made in lab. Can act indirectly or directly on the tumour. Programmed cell death protein e.g. pembrolizumab and nivolumab.

Question 43

How do immunomodulators act indirectly?

Answer 43

Facilitate anti-tumour body response by: Stimulating or suppress the immune system. Interleukins 2 recombinant induces cytolytic T cells against the tumour.

Question 44

What are the complications of cancer chemotherapy?

Answer 44

Inter patient variation. Induced nausea and vomiting, 5-HT3 receptor antagonists can reduce. Leakage with tissue necrosis. Bone marrow suppression. Infection Alopecia Infertility Teratogenesis (deformities) Secondary malignancy

Question 45

What are predictive biomarkers for giving oncology drugs?

Answer 45

DPYD TPMT UGT1A1 G6PD CYP2D6 F5 F2

Question 46

What is primary chemotherapy resistance?

Answer 46

Persistent disease or recurrence. Intrinsic resistance to cancer cells before treatment. Tumour heterogeneity Tumour microenvironment Cancer stem cells microRNA in cancer drug resistance

Question 47

What are the implications of chemotherapy resistance?

Answer 47

Primary resistance can limit the effectiveness of initial chemotherapy regimens. The choice of alternative treatments may be considered from the outset.

Question 48

What is therapy induced resistance?

Answer 48

Initially responsive cancer cells evolve mechanisms to survive and proliferate. Multidrug resistance Inhibition of cell death Changing the drug metabolism Genetic mutations, that change the drug targets, enhance DNA repair.

Question 49

What are the implications of therapy induced resistance?

Answer 49

Limited long-term effectiveness of chemotherapy. Need for change in treatment regimens, including switching drugs or incorporating additional agents to overcome resistance.