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
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- 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
