Cancer Chemotherapy

Question 1

Is the immune response good or bad in response to anti-microbials ? in response to anti-cancers ?

Answer 1

Immune response is good in response to anti-microbials, but bad in response to anti-cancers.

Question 2

Is the body response good or bad in response to anti-microbials ? in response to anti-cancers ?

Answer 2

Body response is good in response to anti-microbials, but bad in response to anti-cancers.

Question 3

What is the percentage of cancerous cells which should ideally be killed by anti-caner treatment ? by anti-microbial treatment ?

Answer 3

% Kill Needed by anti-microbials: Partial

% Kill Needed by anti-cancers: Sufficient for a clinical response

Question 4

Is the biochemistry of the cells targeted by anti-microbials the same or different to normal body cells ? by anti-cancers ?

Answer 4

Biochemistry of cells targeted by anti-microbials: Different

Biochemistry of cells targeted by anti-cancers: Same

Question 5

Describe the main treatment options for cancer.

Answer 5

1) Surgical excision 2) Radiotherapy 3) Chemotherapy

Question 6

Identify the main groups of drugs used in chemotherapy.

Answer 6

• Alkylating agents
• Antimetabolites
• Cytotoxic antibiotics
• Plant derivatives

Question 7

Identify the most commonly used group of drug in chemo.

Answer 7

Alkylating agents

Question 8

Describe the mechanism of action of Alkylating agents.

Answer 8

• Have properties of forming covalent bonds with suitable nucleophillic substances in the cell under physiological conditions.
• Intrastrand crosslinking of DNA:
- Normally guanine residues in DNA exist predominantly in the keto tautomer.
- This allows them to hydrogen bond with cytosine.
- When the 7 nitrogen of guanine is alkylated it becomes more acidic and the enol tautomer is formed.
- This modified guanine can mispair with thymine residues during DNA synthesis. i.e. G-T not G-C
- Alkylation of the 7 nitrogen destabilises the imidazole ring causes ring cleavage
- This leads to depurination (excision of guanine residues)
- The resulting damage triggers cell death by apoptosis.

Question 9

Identify the major groups of alkylating agents. Give one or two examples for each group.

Answer 9

1) Nitrogen mustards – e.g. cyclophosphamide
2) Ethylenimines - e.g. Thiotepa
3) Alkylsulphonates - e.g. Busulphan
4) Hydrazines and Triazines – e.g. Temozolomide
5) Nitrosoureas – e.g. lomustine, carmustine 6) Platinum based compounds – e.g. cisplatin

Question 10

Identify the main groups of antimetabolites. Give one or two examples for each group.
Comment on the chemical structure of these specific examples.

Answer 10

1) Antifolates – e.g. methotrexate (looks like a folate)
2) Antipyrimidines – e.g. 5-FU, gemcitabine, Cytarabine (look like a pyrimidine base)
3) Antipurines – e.g. mercaptopurine, thioguanine, fludarabine (look like purine bases)

Question 11

What is the general mechanism of action of antimetabolites ?

Answer 11

Target arrest of cancer cell DNA replication.

Question 12

Identify the main groups of Cytotoxic antibiotics.

Answer 12

• Anthracyclines
• Dactinomycin
• Bleomycin
• Mitomycin

Question 13

Identify the main Anthracyclines.

Answer 13

Doxorubicin

Question 14

Briefly explain how plant cytotoxic antibiotics generally work.

Answer 14

Diverse mechanisms of action depending on group of cytotoxic antibiotic, but produce their effects mainly by direct action on DNA.

Question 15

Briefly explain how plant derivatives generally work.

Answer 15

Spindle poisons (inhibitors) – affect microtubule function and prevent mitotic spindle formation or top I/ II inhibitors

Question 16

Identify the main groups of plant derivatives. Give a couple of examples for each group.

Answer 16

• Vinca alkaloids (e.g. Vincristine, Vinblastine) • Taxanes (e.g. Paclitaxcel (taxol), docetaxel)
• Camptothecins (e.g. irinotecan)
• Etoposide

Question 17

Describe the mechanism of action of Vinca alkaloids.

Answer 17

Bind tubulin and prevent polymerisation into microtubules

Question 18

Describe the mechanism of action of Taxanes.

Answer 18

Stabilise (freeze) microtubules

Question 19

Describe the mechanism of action of Camptothecins.

Answer 19

Bind to and inhibit topoisomerase I

Question 20

Describe the mechanism of action of Etoposide.

Answer 20

Inhibits mitochondrial function, nucleoside transport and topoisomerase II

Question 21

What are the main drawbacks of current chemotherapy of cancer ?

Answer 21

• Target cell proliferation not the more lethal properties of invasiveness and metastasis
• Non-specific cell killers rather than being aimed at the particular changes which make a cell malignant
• The development of resistance (particularly multidrug resistance) to anticancer drugs
• Leaves some remaining cells, since total elimination of malignant cells is not possible using therapeutic doses, and the host’s immune response is often not adequate to deal with the remainder.
• Healthy cells which have a high rate of growth and multiplication include cells of the bone marrow, hair, GI mucosa and skin therefore side-effects often relate to these body systems (severity of side effects varies between drugs, and there may be drug-specific side effects)
• Patient compliance due to side-effects (i.e. not completing the therapy regimen)

Question 22

Identify some side effects of specific anti-cancer drugs.

Answer 22

Anthracyclines and cardiotoxicity
Vinca alkaloids and neuropathy
High dose cisplatin and ototoxicity

Question 23

What is the normal timeframe of side effects of anti-cancer drugs ?

Answer 23

Side effects often occur 7-14 days post treatment. These can be cumulative over many cycles

Question 24

Identify some specific side effects of anti-cancer drugs.

Answer 24

• Tumour Lysis Syndrome
• Bone Marrow Myelosupression
• Gastro-intestinal (vomiting and nausea, loss of appetite, constipation, diarrheoa)
• Mucositis (ulceration, dry mouth, pain, taste alterations)
• Other (fatigue, body image issues, peripheral neuropathy, altered renal function, infertility, secondary malignancy)

Question 25

Describe Tumour Lysis Syndrome.

Answer 25

• Acute side-effect and a metabolic emergency
• Causes: rapid cell lysis (death) & large amounts of cell metabolites in blood.
• Characterized by: hyperuricaemia, hyperphosphataemia, hyperkalaemia and hypocalcaemia
• If untreated: can lead to acute renal failure, cardiac arrest and death (especially bad for patients with existing disturbed renal function)
• Precautions for Tumour Lysis Syndrome in cancer chemotherapy: risk assessment prior to chemotherapy + monitor and respond to deranged urea and electrolytes / fluid balance (dialysis may be required)

Question 26

Describe the side effect on bone marrow of cancer chemotherapy.

Answer 26

• Myelosuppression – reduced production of cells which provide immunity, oxygen transport and clotting
• Cells affected: Only actively dividing cells in the bone marrow are affected (i.e. stem cells), cells with shorter lifespans are more affected
• Which chemotherapy agents: Most of them, except Vincristine and Bleomycin
• Precautions for myelosuppression: monitor full blood count prior to then daily during treatment cycles + occasional use of recombinant human granulocyte-colony stimulating factors (e.g. Filgrastim) recommended to reduce incidence/duration of myelosupression

Question 27

Identify the main GI side effects of cancer chemotherapy.

Answer 27

Nausea and vomiting
Loss of appetite
Constipation
Diarrheoa

Question 28

Describe the management and treatment used for the side effect of constipation in cancer chemotherapy.

Answer 28

-Laxatives

Question 29

Why does the side effect of constipation occur in cancer chemotherapy ?

Answer 29

Due to reduction in gastric motility, reduced fluid intake and activity (side-effect of both chemoterapy itself, and concurrent anti-emetics)

Question 30

Describe the management and treatment used for the side effect of diarrhoea in cancer chemotherapy.

Answer 30

• Manage by stopping oral chemo
• May need to give IV fluid support
• Consider adding anti-diarrhoeal

Question 31

What is the problem with diarrhoea, why do we need to worry about such a side effect ?

Answer 31

Because diarrhoea can cause severe dehydration and electrolyte disturbances

Question 32

Describe the management and treatment used for the side effect of mucositis in cancer chemotherapy.

Answer 32

• Assess the oral cavity regularly
• Encourage good oral hygiene and regular dental visits
• Anti-bacterials and anti-virals

Question 33

What are the main symptoms of mucositis ?

Answer 33

Ulceration, dry mouth, pain, taste alterations

Question 34

Identify some of the “other” side effects of cancer chemotherapy.

Answer 34

• Fatigue
• Body image side-effects (e.g. hair loss, weight loss/gain, appearance of intervention wounds)
• Peripheral neuropathy
• Altered renal function
• Delayed effects (e.g. infertility, secondary malignancy)

Question 35

Identify any other groups of anticancer drugs besides the main chemotherapy agents classes. Give examples in these groups.

Answer 35

Novel targeted agents (monoclonal antibodies and small molecules):

• Rituximab
• Trastuzumab (Herceptin)
• Imatinib (Gleevec)

Question 36

Describe the process + cancer targeted by each of the novel targeted agents.

Answer 36

• Rituximab targets a B cell surface protein and is used for B cell lymphomas
• Trastuzumab (Herceptin) targets epidermal growth factor receptor 2 (HER2/ ERBB2) and is used for breast cancer.
• Imatinib (Gleevec) inhibits bcr-abl gene (fusion protein gene) signaling pathways and is used for chronic myeloid leukaemia.

Question 37

What is the main benefit of novel targeted agents over the main chemotherapy agents ?

Answer 37

More precise (target specific receptors/pathway) so less side effects, and are aimed to be more specific to individual patient cancers.

Question 38

What does personalised medicine use to make choices about treatment ?

Answer 38

– genomic/genetic testing
– proteomic profiling
– metabolomic analysis (study metabolites)

Question 39

What are the main features of personalised medicine ?

Answer 39

• Predictive
• Personalised
• Preventative
• Participatory

Question 40

Briefly explain how personalised cancer therapy would work.

Answer 40

1) Molecular profiling (of the different cancer patients)
2) Prognostic markers, markers predictive of drug sensitivity/resistance, markers predictive of adverse events
3) Classification of different patients into sub-groups given different drugs

Question 41

Graph and explain the different measures taken in the old, current and future paradigms of medical care as severity of the disease changes over time.

Answer 41

Refer to slides 26, 27 and 28 in lecture on “Cancer Chemotherapy”

1) Old paradigm: Reactive Medical Care
After disease onset, diagnosis occurs, followed by treatment. If treatment 1 is not effective, switch to treatment 2. If treatment 2 is not effective, switch to treatment 3 etc.

2) New paradigm: Efficient Medical Care
Before disease onset, use screening and check for pre-disposition in the population to prevent disease. If past disease onset, diagnosis and prognosis occur which help select the “right” drug for the patient. Then, phase of monitoring.
All this contributes to lack of side effects for the patient (i.e. personalised medicine)

3) Future paradigm: Preventive Medical Care
Preventive measures, along with screening and predisposition, prevent the onset of disease or prevent it getting severe. Then, phase of monitoring.

Question 42

Describe the personalised medicine approach for non small cell lung cancer.

Answer 42

♣ EGFR mutation analysis: activating mutations - erlotinib
♣ KRAS mutation analysis: activating mutations – not erlotinib
♣ ALK rearrangement analysis: (4%) fusion protein - crizotinib
♣ Squamous NCSLC: nivolumab (anti-PD-1/anti-PD-L1 antibody, blocks PD-1/ PD-L1 signaling axis)

(ALK rearrangements are mutually exclusive with EGFR or KRAS mutations)

Question 43

Describe the personalised medicine approach for colorectcal cancer.

Answer 43

♠ KRAS/ NRAS mutation analysis: no mutations (i.e. wildtype) - cetuximab (i.e. anti-EGFR monoclonal antibody therapy) plus chemotherapy

♠ RAS mutation analysis: yes mutation - not cetuximab (presence of RAS mutation predicts the lack of response to therapy)

Question 44

Describe the personalised medicine approach for melanomas.

Answer 44

☺ BRAF mutation analysis: activating mutations, vermurafenib (second line therapy, inhibits mutated BRAF)
☺ NRAS mutations: MEK inhibitors/ combinations (clinical trials)
☺ KIT (c-Kit) mutations (3% melanomas): imatinib (targets c-KIT molecules)
Majority of (40 to 60%) of cutaneous melanomas carry activating mutations (usually due to small change in small section of DNA) of BRAF gene, which then leads to further tumour growth (so vermurafenib most common treatment above).

Also:
☺ Metastatic melanoma: ipilimumab (anti-CTLA-4 antibody)
☺ Nivolumab (anti-PD-1/PD-L1 antibody) to block PD-1/ PD-L1 signaling axis

Question 45

Define melanoma.

Answer 45

Common and often fatal skin cancer where the cancer cells have frequent genetic mutations.

Question 46

Describe the personalised medicine approach for brain tumours (High grade glioblastomas).

Answer 46

First line: Temozolomide (alkylating agent) + radiation therapy

O6-Methylguanine-DNA-methyltranferase (MGMT) is a DNA repair enzyme which is thought to repair DNA damage caused by chemotherapy alkylating agents such as temozolomide.
Promoter methylation of the MGMT gene decreases the expression of the MGMT protein and correlates with longer survival of patients with high grade gliomas treated with temozolomide.
Therefore, MGMT promoter methylation is assayed to give a percentage methylation (higher methylation = higher efficacy)
(BUT % readout not that reliable – dangers of a test that is not robust)

Question 47

Describe the personalised medicine approach for gastric tumours.

Answer 47

• c-KIT- positive metastatic GI Stromal Tumours (GISTs) are treated with imatinib (GISTs are tested for KIT (c-kit) mutations in exons 9, 11, 13 and 17. )
• Metastatic adenocarcinoma of the stomach or gastro-oesophageal junction who have not received prior treatment for their metastatic disease and have tumours expressing high levels of HER2: Trastuzumab (anti-Her2) + cisplatin + capecitabine or 5-fluorouracil

Question 48

What proportion of all gastric tumours do GISTs make up ?

Answer 48

3%

Question 49

Describe the diagnostic aspect of personalised medicine for soft tissue and bone tumours.

Answer 49

Molecular studies (e.g. FISH) used to complement morphological diagnosis of soft tissue and bone tumours. 
FISH testing is a standard of care in a group of soft tissue sarcomas (e.g. Ewing’s sarcomas, alveolar rhabdomyosarcomas, leiomyosarcomas, fibromyxoid sarcomas).

Question 50

How does Nivolumab work?

Answer 50

Checkpoint inhibitor. Cancer cells, because they are similar to human cells, evade normal immune cell (down-regulate things on their surface). If give this checkpoint inhibitor, unmask cancer cells so immune system can see them as a threat and can try to eradicate them from the body.
Therefore, Nivolumab is a fully human IgG4 PD-1 immune checkpoint inhibitor antibody that disrupts PD-1 mediated signaling and restores antitumor immunity (anti-PD-L1/anti-PD-1).