Chemotherapy from a clinical perspective Flashcards
why is it predictive that incidences of cancer will rise despite the advancement in treatment
aging population where older patients are kept alive longer - cancer is an aging disease
What kills patients with cancer
- local complication of tumour (blocking blood vessel, airway or bowel)
- systemic complication of cancer (infection, cachexia and paraneoplastic syndromes)
- direct complication of the treatment (neutropenic sepsis, bleeding and renal failure)
- 90% = Metastasis
metastasis require _ treatment
systemic treatment
what are the types of cancer treatment
- Surgery
- Radiotherapy
- supportive therapy (analgesia, anti-emtics, psychological support for symptoms control)
- Systemic therapy (chemotherapy, immunotherapy and targeted agents
what are some Chemotherapy drugs and what do they do (big picture)
Alkylating agents, anti-metabolites, platimums, topoisomerase inhibitors and tubulin-binding agents
- target DNA replication,
- antiproliferative agents
- Non-selective normal tissue toxicity
what makes an effective chemotherapy drug
Drug reaches the tumour cell - don’t metabolise early
Sufficient quantities of active component enter the cell
Tumour cells are sensitive to the drug before resistance emerges
Normal tissue must be able to tolerate and recover (efficacy vs tolerabilty
What is ‘combination’ treatment in chemotherapy
○ Can combine 2+ chemo drugs (which work in different ways) and can also be combined with radiotherapy
○ Several different drugs, each independently active against a given disease (Each drug should have: A different mechanism of action + A different dose-limiting toxicity)
○ As a result: Each drug is given at full dose, the rate of cell kill increases (addressing tumour heterogeneity), The chance of emergence of a drug-resistant clone decreases
what is taken into consideration when patients need chemoterapy
- Patients’ fitness and co-morbidity
- Kidney/liver/ bone marrow function - look at RBC and WBC count as well as platelets
(Drugs needs to be metabolised (liver) and filtered out (kidneys)) - In advanced disease consider quality vs. quantity life
What can be done, using chemotheray, towards a curaive intent
High dose/Radical chemotherapy (Germ cell tumour/lymphomas)
Neo-adjuvant Chemo + surgery/ Radiotherapy (Oesophageal, ovarian, lung and breast)
Surgery + Adjuvant Chemo (ovarian, lung, colorectal, breast)
T/F chemo is only used with curative intent
False - Palliative chemo can be used to prolong survival
Explain the proportional cell kill models
○ Within tumour different populations of cells; some continually proliferating cells; resting cells;
○ Growth of tumour depends on the actively growing fraction of the tumour: growth fraction and the tumour doubling time
○ Tumours are detectable at a critical mass = 10-9 cells = 1 g
○ Chemo going to have max effect on the actively proliferating cells so if high growth fraction = high chemo sensitivity
○ BUT that also means affect organs with high growth fraction e.g. bone marrow and gi mucosa
○ Types of cancers can influence number of chemo cycle
how are systemic chemotherapeutic agents classified (broadly)
- Mechanism of action
- Source/origin
- Cell cycle phase specificity
how are chemotherapy further classified when they effect cell cycle
Cell cycle active (phase specific)
Cell cycle active (phase non-specific)
Non- cell cycle active (e.g corticosteroids)
How was chemotherapy discovered
Blood + Bone marrow in yellow cross gas (mustard) poisoning)
○ Soldiers exposed to yellow cross gas (mustard gas) had aplastic bone marrow
○ Those who survived had a transient reduction in the white blood count
○ Suggested use of similar agent for treatment of leukaemia
○ Lead to the development Nitrogen mustard - mustine (Alkylating agents)
how do alkylating agents work
Alkylation - transfer of one alkyl group to naother molecule
- Transfer an alkyl group to the N7 of guanine residues in DNA via production of reactive ethyleneimonium and carbonium ions
-This mechanism of toxicity is also responsible for the ability of some alkylating agents to perform as anti-cancer drugs in the form of alkylating antineoplastic agents, and also as chemical weapons such as mustard gas.
Alkylated DNA _
- either does not coil or uncoil properly, or cannot be processed by information-decoding enzymes.
- This results in cytotoxicity with the effects of inhibition the growth of the cell, initiation of programmed cell death or apoptosis.
- However, mutations are also triggered, including carcinogenic mutations, explaining the higher incidence of cancer after exposure
How do antimetabolites work
- Disrupting the building blocks of DNA
= Methotrexate an enzyme inhibitior which inhibits dihydrofolate - Have to give folic acid to rescue normal tissue to restore folate stores
- These block thymidine and purine synthesis
Blocking thymidine and purine synthesis causes what
- Folic acid undergoes reduction to first, dihydrofolate and then tetrahydrofolate, by the enzyme dihydrofolate reductase ( DHFR)
(DHFR is the primary target of the folic acid analogue MTX). - Tetrahydrofolate is a purine precursor
- TS (thymidylate synthase) catalyses the conversion of dUMP (deoxyuridine monophosphate) to dTMP (deoxythymidine monophosphate) using 5,10-CH2THF (5,10 methylenetetrahydrofolate) [ which is essential to the TS reaction] and therefore thymidine synthesis.
- Without thymidine, there is uracil misincorporation into dna strands during replication leading to double strand breaks during uracil excision repair-
