Chemotherapy drugs

Question 1

What is cancer?

Answer 1

Uncontrolled proliferation of a normal cell
Turns into a tumour-
- could metastasise
- invasive/not invasive
Caused by DNA mutation
Causes: inherited eg BRCA1/2 gene in breast, viruses, carcinogens, alcohol, sun exposure

Question 2

Normal cell growth regulation

Answer 2

Growth factors = specific receptors/signalling pathways
Cell cycle transducers
Apoptic genes = programmed cell death in ageing/normal cells
Telomeres = cap xsomes (shorten with age until replication stops)

Question 3

Oncogenes

Answer 3

Proto oncogene can mutate into an oncogene, it is a protein which can cause:
- incressed cell division
- increased cell differentiation
- decreased cell death
Oncogenes are anti-apoptopic = cell survival

Question 4

Cell mutations leading to cancer

Answer 4

In promoter region increased transcription
Gene amplification = increased copies of proto-oncogene
Xsome translocation = proto-oncogene moved to a site more likely for gene expression
Fusion of onco-gene with another gene with increased activity

Question 5

Tumours

Answer 5

Mutations in apoptotic genes
Telomerase expressed = enzyme which stabalizes telomered
Overexpression of growth factors = unrestrained cell growth
Angiogenesis occurs - growth of new blood vessels

Question 6

Metastasis

Answer 6

Primary tumour 
- produces enzymes that break down ECM
Invades nearby tissue
Angiogenisis
- cells transported via new blood/lymphatic system
Secondary tumour

Question 7

What are the 3 aims of cancer therapy?

Answer 7

Curing patient
Prolonging life
Palliative therapy

Question 8

Compartments of tumours

Answer 8

Solid tumours, cells occupy 1 of 3 compartments
A = dividing cells
B = resting cells capable of division
C = cells no longer dividing but contribute to tumour volume

Question 9

Toxic effects of chemo

Answer 9

Drugs affect all rapidly dividing tissues

• bone marrow supression
• impaired wound healing
• loss of hair
• damage ro GI epithelium
• stuntes growth
• sterility
• teratogenicity

Question 10

Targets for anti-cancer drugs?

Answer 10

Hormonal regulation of tumour growth

Defective cell cycle controls

Question 11

Alkylating agents in anti-cancer drugs

CYTOTOXIC

Answer 11

Block DNA synthesis
Targets cells in S phase
Form covalent bonds with DNA to prevent uncoiling and inhibit replication
SE with prolonged use: sterility, increased risk of non-lymphocytic leukaemia

Question 12

What are the 4 types of alkylating agents?

Answer 12

Nitrogen mustards-
Eg Cyclophosphamide
- prodrug, given orally, activated in liver to phosphoramide + acrolein
- acrolein = haemorrhagic cystitis
Eg Mechlorethamine 
-i.v, v reactive
Nitrosoureas -
- highly lipophillic = CNS tumours
Eg Lomustine (orally), Carmustine (iv)
Platinum compounds-
Eg Cisplastin
- v potent, binds to RNA>DNA>protein
- binds to G, A, U
- resistance may develop = DNA repair by DNA polymerase 
- testicular/ovarian cancer, given iv
- SE = severe nausea, vomiting, peripheral neuropathy
Eg Carboplatin
Busulphan

Question 13

Antimetabolites

• CYTOTOXIC
• folate antagonists

Answer 13

Methotrexate
- given orally, i.m, i.v, low lipid solubility
- NSAIDs can decrease excretion = increase toxicity
- can develop resistance
In high doses given with folinic acid to rescue normal cells
Suppresses immune system

Question 14

Antimetabolites

• CYTOTOXIC
• pyrimidine analogues

Answer 14

Compete with C and T bases which make up RNA and DNA = inhibit synthesis
Eg Fluorouracil
Less well absorbed compared to Methotrexate

Question 15

Antimetabolites

• CYTOTOXIC
• purine anologues

Answer 15

Compete with A and G bases = inhibit purine metabolism
Eg Fludarabine
Used mainly in leukaemia

Question 16

Cytotoxic antibodies

- CYTOTOXIC

Answer 16

Eg Doxorubicin
- binds to DNA, inhibits RNA/DNA synthesis
- inhibits topoisemerase ll
SE= cardiac dyasrhythmias , heart failure in high doses
Eg Blecmycin
- degrades pre-formed DNA
- active against non-dividing cells
- 50% patients develop mouth sores, hair loss

Question 17

Plant derivatives
- cytotoxic
Vinca alkaloids

Answer 17

Eg Vincristine, Vinblastine

• prevents polymerisation of tubulin = prevents spindle formation
• effects occur in mitosis

Question 18

Plant derivatives

• cytotoxic
• taxanes

Answer 18

Eg Paclitaxel

- used to treat advanced breast/ovarian cancer

Question 19

Hormones in anti-cancer drugs

Answer 19

Used to treat cancers in hormonw sensitive tissues (breast prostate ovaries)
Tumour growth inhibited by R antagonist, hormones with opposing actions, on drugs which block synthesis of endogenous hormones
Rarely cure disease but decrease symptoms

Question 20

Oestrogens - hormones

Answer 20

Eg Ethinyloestradiol + Diethystilbestrol

• antagonist of androgen-dependant prostate cancer (palliative care)
• SE = nausea, fluid retention, impotence

Question 21

Progestogens - hormones

Answer 21

Eg Northisterone, Megesterol

- used to treat endometrial cancer

Question 22

GnRH anologues

Answer 22

Eg Goserlin

• inhibit GnRh release = decrease LH/FSH to decrease testosterone
• used to treat prostate/advanced breast cancer

Question 23

Hormone antagonists

Answer 23

Eg Tamoxifen

• competative antagonist at oestrogen receptors- inhibits transcription of oestrogen responsive genes
• breast cancer treatment
• adverse affects similar to menopause, endometrial cancer, increased risk of blood clots

Question 24

Glucocorticoids - hormones

Answer 24

Eg Prednisolone, Dexamethasone

• inhibit lymphocyte proliferation = used in treatment of leukaemia /lymphomas
• counter some SE of other drugs
• used in supportive/palliative care

Question 25

Monoclonal antibodies in anti-cancer drugs (immunotherapy)

Answer 25

Produced by cultured hybridoma cells
React with specific target proteins expressed on cancer cells = activates immune system = lysis of cancer cells
Some inhibit survival/promote apoptosis
Targeted therapy = decreased SE
Expensive, given in combination with other drugs

Question 26

Rituximad - monoclonal antibody

Answer 26

Lysis of B lymphocytes

Can cause chills, fever, hypotension

Question 27

Trastuzumab (Herceptin) - monoclonal antibody

Answer 27

Induces immune response + cell cycle inhibitors
Given witn standard drugs increases survival rate
SE= tremor, flu-like symptoms, BP changes, palpitations

Question 28

Control of side effects

Answer 28

Nausea and vomiting:
- decrease patient compliance
- Ondansetron/Graniestron 5HT3 receptor antagonists effective s cytotoxic drug induced vomiting
- Metaclopramide 
Anxiety:
- Lorazepam
Myelosuppression:
- stem cell transplant
- stem cells harvested from patient and infused back after chemo