Physiology 3 - Therapeutic Classes of Drugs for the Treatment of Cancer 1 (Woolard)

Question 1

What are the four chemotoxic approaches?

Answer 1

Alkylating agents, anti-metabolites, topisomerase inhibitors and microtubule poisons

Question 2

What is the fatal consequence of mustard gas exposure (seen in WW1 soldiers)?

Answer 2

DNA alkylation that prevents cell division and leads to apoptosis.

Question 3

What kind of drugs target the M phase (mitotic section) of the cell cycle?

Answer 3

Microtubule poisons

Question 4

What kind of drugs target the S (DNA synthesis) phase f the cell cycle?

Answer 4

Alkylating agents
Anti-metabolites
Topoisomerase Inhibitors

Question 5

Which common toxicities are associated with chemotherapy agents?

Answer 5

Neutropenia, anaemia and thrombocytopaenia (collectively referred to as myelosuppression)
This leads to an increased risk of infection (7-10 days post chemotherapy)
Nausea and vomiting
Diarrhoea and mucositis (pain and inflammation of mucus layers that line the digestive system).
Alopecia
Sterility/infertility

Question 6

Which drugs are alkylating-like agents?

Answer 6

CISPLATIN
Cyclophosphamide
Carboplatin
Oxaliplatin

Question 7

How do alkylating agents work?

Answer 7

They bind to DNA, via a platinum atom, causing intra-strand cross linking
There are specific sites on purine (A, G) bases of DNA
This prevents cell division in S phase, leading to G2 arrest, and as a consequence, the cell undergoes apoptosis.
Cause a conformational change in DNA, making repair difficult, impairing synthesis/replication.
Targets rapidly proliferating cells.

Question 8

What cancers are often treated with alkylating agents?

Answer 8

Brain, breast, bladder, cervix, endometrium, lung, testis, ovaries, multiple myeloma (blood system disease derived within bone marrow) etc

Question 9

What are the adverse effects of alkylating agents such as Cisplatin?

Answer 9

1. Nephrotoxicity - uptake in the PCT, largely controlled/treated with diuretics and pre-hydration
2. Neurotoxicity - acts on the dorsal root ganglion to cause both transient and chronic neuropathies
3. Peripheral neuropathy - damage to outer hair cells of the cochlea (inner ear), resulting in functional deficits due to production of reactive oxygen species (can lead to loss of hearing).

Question 10

Which drugs are antimetabolites?

Answer 10

METHOTREXATE

5- Fluoruracil, Gemcitabine, Mercaptopurine

Question 11

How does Methotrexate work?

Answer 11

Folic acid is required for normal DNA synthesis and repair (function is to transport carbon for methylation reactions and nucleic acid synthesis).

Methotrexate is an analogue of folic acid and acts as an inhibitor of folic acid by binding to DHF reductase. This prevents the production of thymidine.
- Impairs nucleic acid synthesis therefore inhibits DNA, RNA and protein production.

Question 12

How does 5-Fluoruracil work?

Answer 12

It is an analogue of uracil and results in the generation of a nonsense nucleotide.

Question 13

What are antimetabolites used to treat?

Answer 13

May be used alone or in combination with other chemo agents
Leukaemia and lymphoma
Solid tumours; breast, head and neck, lung, bladder, oesophagus

Question 14

What are the adverse effects of antimetabolite agents such as Methotrexate?

Answer 14

1. Nephrotoxicity - nephron
2. Hepatic - causes fibrosis and increases the risk of cirrhosis
3. Pulmonary - less common, but can be fatal. Patients report fever, dry cough, dyspnea, chest pain.
4. Neurotoxicity - chronic demyelinating encephalopathy with dementia, motor paralysis, seizures, aphasia, stroke-like symptoms

Question 15

What kind of drug is Topotecan?

Answer 15

A topoisomerase I inhibitor

Question 16

How does Topotecan work?

Answer 16

Topoisomerase I enzyme causes single strand breaks
Topoisomerase is needed in order to regulate DNA supercoiling to ensure there are no breaks or religation.
Topotecan intercalates between DNA bases and interferes with DNA structure, this impairs replication and synthesis, leading to cell death.

Question 17

What kind of drug is Doxorubicin?

Answer 17

A topoisomerase II inhibitor

Question 18

How does Doxorubicin work?

Answer 18

Topoisomerase II enzymes cause double strand simultaneous cleavage involving hydrolysis of ATP.
Doxorubicin is an anthracycline antibiotic
Inhibits topoisomerase II by binding strongly to duplex DNA via intercalation selectively at C-G sequences and blocks the synthesis of DNA and RNA.
It can generate free radicals, bind to cellular membranes, alter fluidity and ion transport and lead to cell death.

Question 19

What adverse effects are associated with Topoisomerase Inhibitors?

Answer 19

Doxorubicin
Cardiotoxicity - directly effects heart, increasing the likeliness of developing congestive heart failure after 1 year.
Disrupts sarcomere structure leading to myofilament disorganisation within cardiomyocyte.

Question 20

What drugs fall into the category of anti-neoplastics / microtubule poisons?

Answer 20

VINCRISTINE

Vinblastine

Question 21

How does Vincristine work?

Answer 21

A derivative of the periwinkle plant
Binds to tubulin structures and prevents polymerisation into microtubules
Inhibits critical cell division processes, blocking the M phase (mitosis)

Question 22

What clinical combination with vincristine has proven useful?

Answer 22

Vincristine and Prednisone has been effective in children with acute lymphoblastic leukaemia.

Question 23

What are the adverse effects associated with Vincristin (microtubule poison)?

Answer 23

1. Cardiovascular - orthostatic hypotension
2. Peripheral neuropathy - parasthesias, hand tingling and other neuropathic pain
3. GI - constipation