Chemotherapy Flashcards
What are approaches to treat cancer?
What are the general problems with anti-cancer treatments?
- Lack of selectivity and specificity
* Diff to target the cancer without affecting normal cell function - Off-target side effects
- Drug resistance
* Cancer cells express transporter proteins which can help ‘pump’ toxic agents (treatments) out of the cell - Patient-specific factors
* Traditional approaches have focussed on general patterns of genetic mutations
5.Problems with cancer diagnosis
* Non-specific symptoms make it difficult to diagnose
* Lack of effective biomarkers for cancer diagnosis
What are the options for treating patients with cancer?
- Surgery
- Radiotherapy
- Chemotherapy
Explain how surgery can treat patients with cancer?
- Surgery is invasive, but offers best ‘cure; for solid tumour
- Remove isolated metastatic masses
- Facilitate further treatment i.e. providing access for chemotherapy delivery (implanted fusion pumps)
- Can be used for prevention i.e. removal of moles, polyps or other precancerous lesions
- Debulking: removing bulk of tumour size before chemo.
Explain how radiotherapy can help treat patients with cancer.
- External beam radiotherapy
* From outside the body using high energy iosinsing radiation
* Commonly used in up to 60% of treatments - Internal brachytherapy
* Radiotherapy from small radioactive ‘seeds’ placed within the body
Both cause DNA damage but normal tissues also affected
Explain how chemotherapy can help treat patients with cancer.
Interferes with cell cycle
* Aims to inhibit cellular events that lead to cell division and replication
* Most target S or M phase of cell cycle
- S phase - Responsible for DNA replicationn(chromosmome rep)
- M phase - Responsible for mitosis and cytokinesis.
Explain common causes of DNA damage.
What are the issues with chemotherapy?
(For exams give specific issues with specific treatments. Dont go generic unless clearly linked)
- Most cytotoxic chemotherapy drugs target cells that are actively multiplying
* Rapidly dividing cells are particularly susceptible to cell death
* Bone marrow, GIT, hair folicles are examples of normal cells that are actively multiplying
2.Common toxicities associated with chemotherapy agents include:
* Neutropenia, anaemia and thrombocytopaenia
(collectively referred to as myelosuppression)
* Increased risk of infection
* Nausea and vomiting
* Diarrhoea and mucositis (pain & inf in mucus layers in dig system)
* Alopecia
* Nephrotoxicity, neurotoxicity and CARDIOVASCULAR toxicity
What are alkylating agents?
(1)
E.g of these platinum drugs include Cisplatin
- Metal-based chemotherapeutic drug
- Binds with genomic DNA to create DNA lesions –> Forming both inter + intra crosslinks that create contortion of DNA, Changing conformation and making DNA repair difficult
- Blocks production of DNA and associated proteins, stops DNA synthesis and replication
- Activates several pathways that lead to cell death
1. Bind to specific sites on Purine (A, G) bases of DNA
2. Prevent cell division, cause cell death–>Activates apoptosis
Cytotoxicity targeted to rapidly proliferating cells
What are alkylating agents? (and links to DNA)
(2)
- Links to DNA
* Via a platinum atom, not a carbon atom
* Not simply an alkyl group consisting of C/H
2.DNA damage
* Affect cell cycle is S-phase (block DNA synthesis), Leading to G2 arrest
* Cross-link the 2 strands (inter and intra)
- One of the most widely used class of cytotoxic agents used to treat:
- Brain, breast, bladder, cervix, Endometrium, Lung, testis, ovary, multiple myeloma and other cancers
What are adverse effects associated with alkylating-like agents? (Cisplatin)
Most notable side-effects are nephrotoxicity, hepatotoxicity and GI toxicities
Nephrotoxicity
* Renal excretion is the primary way cisplatin is removed from body—>Kidneys can accumulate a greater amount than other organs (28-36%)
Hepatotoxicity
* Mainly caused by oxidative stress
GI toxicities
* Incd nausea and vomiting, despite prophylactic antimimetic use
What are antimetabolites?
- An e.g. of these is Methotrexate
- Folic acid required for normal DNA synth and repair
- Func to transport carbon for methylation reactions and nucleic acid synth
- Methotrexate is a structural analog of Folic acid and acts as an antimetabolite, interfering with metabolism of folic acid
1. After entry into cells, methotrexate is polyglutamated and binds to dihydrofolate reductase
2. Competetively inhibits the conversion of dihydrofolate to tetrahydrofolate
3. Tetrahydrofolate is essential for biosynthesis of thymidine and purines—> Blocks thymidine production - Impairs nucleic acid synth therefore inhib DNA, RNA and protein production
What are antimetabolites? (Methotexate) (2)
- Interfere with nucleotide/DNA synth
1. Methotrexate is folate antagonist
2. Causes DNA damage- affects S-phase (blocks DNA synth) - Admin alone or in combo with other chemotherapeutics to treat:
1. Leukaemia, lymphoma
2. Solid tumours, Breast, head, neck, lung, bladder and oesophagus - Methotrexate can be given via many routes: Intramuscular, intravenous, subcutaneos, orally etc
1. Dose range is broad
What are adverse effects of antimetabolites? (Methotexate) (3)
Nephrotoxicity - Cytotoxic to cells in nephron of kidney
* Methotrecxate and its metabolites gather in renal tubes causing crystal nephropathy
Hepatic - Causes fibrosis and increased risk of cirrhosis (more common with longer term treatment)
Pulmonary - Less common but can be fatal. fever, dry cough etc
Mucositis - Can become a rate-limiting toxicity - due to damage to mucosal barrier
Neurotoxicity - Chronic demyelination encephalopathy with dementia, motor paralysis, seizures, aphasia, stroke like symptoms
What are Topoisomerase I inhibitors?
E.g. inc Topotecan
- Enzymes that regulate DNA supercoiling, causing single strand breaks and re-ligation
- Used to treat metastatic ovarian cancer, small cell lung cancer, cervical carcinoma, short half-life
- Cytotoxicity targeted to rapidly proliferating cells
What are the basic methods of Chemotherapy?
