Lecture 22 - Chemotherapy - Mechanisms of Action NOT FINISHED Flashcards
What are the possible uses for chemotherapy?
- primary induction treatment
- neoadjuvant treatment - debulking prior to surgery or radiotherapy
- adjuvant treatment following surgery to reduce risk of metastases, mop up micro metastases
- regional treatment
What is meant by dose-escalation and dose-limiting toxicity?
- efficacy dose similar to toxic dose
- need to give greatest effictive dose that is not lethally toxic
What properties of malignant cells does chemotherapy target?
- paracrine/autocriine and hormone factors
- surface antigens, MHC
- altered gene expression
- impaired apoptosis
- mitogenic signals
- dysregualted cell cycle
What is required of the cell cycle in order to a cell to be susceptibe to killing by chemotherapy?
- an intact apoptotic pathway
Draw the cell cycle and list the agents that work at each point on it;
- microtubule inhibitors
- topoisomerase inhibitors
- alkylating agents
- anti-metabolites
- platinum analogues
see lecture
-
-
- external signalling
- DNA damage e.g. via p53
- differentiation
How do platinum analogues work as chemotherapy?
- diffuse into cell
- those Cl- groups
- cross links DNA, prevents DNA, RNA, protein synthesis
- leads to apoptosis
How do antimetabolites work as chemotherapy?
- bear a structural similarity to naturally occurring substances such as vitamins, nucleosides or amino acids
- main classes include folic acid antagonists, purine analogues, pyrimidine analogues
What class of chemotherapy is methotrexate and what is its mechanism of action?
Antimetabolite, folic acid antagonist
- acts at S phase
- block synthesis of coenzymes involved in the synthesis of DNA and RNA
What class of chemotherapy is 5-fluorouracil and what is its mechanism of action?
Antimetabolite, pyrimidine analogue
- inhibit synthesis of nucleic acids
- inhibiting enzymes of DNA synthesis
- or becoming incorporated into DNA and interrupting DNA synthesis
What is the action of anthracyclines?
- topoisomerase II inhibition
- DNA intercalation –> ss and ds DNA breaks
- free radical formation - bind to DNA (offtarget toxicity)
What stage of the cell cycle to topoisomerase inhibitors work on?
- stop entering mitosis from G2
How do topoisomerase I inhibitors work?
- binds to the enzyme DNA complex, stabilising it and prevent DNA replication
How do topoisomerase II inhibitors work?
- stabilise the complex between topoisomerase II and DNA that causes strand breaks and ultimately inhibits DNA replication
How do alkylating agents work?
- covalently linking an alkyl group to a chemical species in proteins or nucleic acids
- interfere with DNA replication
What are the two types of microtubule inhibitors?
- vinca alkaloids
- taxoids
How do vinca alkaloids work?
- mitotic spindle poisons
- bind to tubule, a component of spindles
- inhibits assembly of spindles
- affects DNA repair
How do taxoids work?
- promotes assembly and inhibits dissasembly
- prevents dynamic reorganisation
What are the causes of the off target effects of anthracyclines?
Give examples of these off target effects
Caused by free radical formation that bind to DNA
- myelosupresiso
- gastrointestinal
- alopecia
- local tissue damage
- cardiotoxicity
Therapeutic index
- drugs directed against cell division also effect normal cells
- normal cells vary in susceptibilty, many are less sensitive than cancer cells
- normal cells may recover from cytotoxic injury more rapidly than cancer cells
Give examples of the reversible toxicities of chemotherapy
Affects rapidly dividing cells:
- bone marrow
- GI tract
- germinal epithelium
- lymphoid tissue
- hair follicles
What does reversibility of toxicities reflect?
What does this determine?
- reflects compartment repopulation by recruitment of resting stem cells and dictates time for recovery between treatment cycles
Give examples of irreversible cumulative toxicities
What effects do they reflect?
What do they dictate?
Target slow growing cells:
- kidney
- nerves
- heart
- lungs
Reflects the individual physicochemical properties of different classes of drugs
Dictates maximum safe cumulative exposure
What is growth fraction?
How does it change in different tumour sizes?
When is it highest?
- the proportion are tumour cells that are dividing
- clinically undetectable tumours ave the highest growth fraction
- large tumour mass –> small number of cells susceptible to cytotoxic therapy
What are the aims of combination chemotherapy?
- to achieve maximum cell kill with tolerable toxicity
- increases the kill fraction of resistant cells in a heterogenous tumour population
- prevent or slow the outgrowth of resistance malignant clones
What are the principles of combination chemotherapy?
- only drugs shown to be partially effective - participatory achieving full responses
- avoid overlapping toxicities on a single organ system
- optimal dose and schedule
- treatment-free terava should be shortest comptabilie with recovery of the most sensitive normal tissue
- monitor respones, performance status and toxicity
- sequential regimens out-perform alternating regimens
- Dose reductions for toxicity can reduce chance of …….
- Dose delays enable fast growing micro-metastases to …….
cure
recover
As tumour size increases, mean fraction resistant cells ………..
increases
Phase I trials use ……… …… as surrogate marker for efficacy
Phase II trials use ……… ……… as surrogate marker for clinical benefit
- acute toxicity
- tumour shrinkage
