anti-cancer drugs Flashcards
6 main classes of cytotoxic chemo drugs
cell cycle specific (kill cells during specific parts of cycle -> only affect actively dividing cells)
1. anti-metabolites
- methotrexate
- 5-fluorouracil
- microtubule inhibitors
-vinblastine
- paclitaxel - topoisomerase I/II inhibitors
- topotecan/irinotecan
- etoposide
cell-cycle non-specific (work throughout cell cycle -> not only rapidly proliferating cells)
- alkylating agents
- cyclophosphamide - platinum analogues
- cytotoxic antibiotics
common AE: myelosuppression
alkylating agents
eg cyclophosphamide
MOA: alkyl group forms covalent bonds with DNA, crosslinking it and disrupts DNA replication and transcription
platinum analogues
- cisplatin, carboplatin, oxaliplatin (stronger at lower dose)
MOA: intrastrand DNA-protein crosslinks whicn leads to DNA breaks
excretion: urine
AE: nephrotoxic, peripheral sensory neuropathy
anti-metabolites
methotrexate: targets dihydrofolate reductase
(cancer cells use more folate)
5-fluorouracil: inhibits thymidylate synthase (TS)
block formation of nucleotides -> block DNA synthesis
cytotoxic antibiotics
anthracyclines: doxorubin
MOA:
- intercalate into DNA -> inserts itself between nucleotides bases to interfere with DNA replication and transcription
- create reactive oxygen species to damage DNA
- inhibit topoisomeraseII
- alter membrane fluidity and ion transport
AE: cardiotoxicity
microtubule inhibitors
inhibitors bind to beta subunit of tubulin.
vinblastine -> bind polymerising end to prevent elongation of microtubule
paclitaxel -> stabilise microtubule to prevent depolymerisation (preventing shortening of spindle fibres stops the sister chromatids from being pulled apart and to the poles during anaphase)
topoisomerase I/II inhibitor
topoisomerase I -> single strand cut (eg topotecan, irinotecan)
topoisomerase II -> double strand cut (eg etoposide)
MOA:prevent unwinding of DNA needed for DNA replication and transcription
key approaches to targeting tyrosine kinases
- block antibodies
- soluble receptors
- inhibitor of receptor kinase
- inhibit downstream signalling
- epigenetic modulators
eg imatinib -> BCR-ABL tyrosine kinase inhibitor
MOA: bind to ADP to prevent ATP from binding -> prevent signalling
2 approaches to T cell immunotherapy
- T cell immunotherapy
(CAR-T, immune checkpoint inhibitors) - therapeutic antibodies (neutralising, antibody drug conjugates, radiotherapy)
-> ideal for surface receptors and extracellular ligands
neutralising antibodies
block interaction between ligand and receptor -> targets angiogenesis by blocking VEGF receptor on endothelial cells
- slow down cancer progression
effector cell mediated cytotoxicity
complement dependent cytotoxicity
- complements flow around interstitial fluid and blood
- when recognise antibody on tumour cell, can induce complement dependent cascade, leading to the formation of MAC pore
antibody-dependent cell-mediated cytotoxicity
- antibody binds to tumour cell and Fc region binds to Fc receptor on NKL cells and crosslinking triggers degranulation of NK cell and induces apoptosis and necrosis in cancer cell
antibody drug conjugates
eg brentuximab (binds to Cd30 on T cells)
MOA: add chemotherapy drug to antibodies
chemodrugs have poor theraputic index as a free drug so use antibody to change distribution of drug -> increase theraputic index and can more specifically go to cancer cells
molecular targeted radiotherapy
systemic treatment where radiolabelled molecules release radiation within a localised area and cells within radius will die
pros -> antibody does not need to be bound to cancer cells to kill it
cons -> bystander effect: potential destruction of adjacent cell
T cell immunotherapy: CAR T cell
use patient’s own immune cells to target and kill cancer cells
chimeric antigen receptor (CAR) T cells -> T cells engineered to express CAR that can recognise and bind to antigens on tumour cells (dont need APC)
features of CAR
extracellular domain taken from antibody which recognises tumour-specific antigen
intracellular domain: secondary signal to promote survival and replicative capacity of CAR T cell (in normal cell, have negative feedback where T cell will die once done)
intracellular domain
1st gen only CD3 (no costimulation)
2nd gen CD3 + CD28
3rd gen CD3 + CD28 + CD 137 (2 costimulation)
steps to CAR T immunotherapy
- extract T cells
- reprogramme T cells- viral vector inserts CAR gene into T cell
- manufacturing CAR T cell- CAR T cells proliferated in vitro
- patient pre-conditioning-m patients given chemo to lower white blood cell count (bone marrow) to more readily accept CAR T cell
- body recognises that CAR t cell is foreign and would reduce the T cell load so bring body to deficit of T cells - treatment- patient given CAR T cells
immune checkpoint inhibitors
CTLA-4
eg ipilimumab
MOA: block interaction between CTLA-4 and APC -> T cell response remains active
PD1 (programmed cell death protein 1)
eg nivolumab
MOA: binds to PD1 expressed by T cell and to prevent PD-L1 from binding and inhibiting T cell activation
what are 2 key investigations we can run to test the genetic/molecular attributes of a cancer?
FISH: fluorescence in situ hybridisation
immunohistochemistry
- make antibodies bind to target antigen and get colour producing enzyme to bind to antibodies
- colour under the microscope indicates presence of antigen and colour intensity related to amt of antigen present
chemotherapy
use “poisons” to kill or inhibit tumour growth with minimal effects on normal cells
- by interrupting cellular processes to induce apoptosis within cancer cells
- greatest selectivity against proliferating cells because high poliferation in tumour cells but also attack normal cells that actively dividing (eg bone marrow, skin, hair follicles, GI mucosa)
- narrow theraputic window
advantages of chemotherapy combinations
advantages
- give lower dose of each drug for maximal cell kill
- more broad spectrum effects against heterogeneous tumour cells
- prevent or slow development of drug resistance
principles of chemo combinations
efficacy: if drug can only work for a particular tumour, can only combine with the drug with other drugs that can only work on that tumour
toxicity: non-overlapping toxicity to minimise lethal effect and maximise dose intensity
optimum scheduling: shortest time to recovery
mechanism of interaction: choose drugs that work in distinct pathways to avoid any unexpected AE
avoidance of dose changes: reducing dose of drug to add another drug to the combination would reduce the efficacy
chemotherapy regimens
breast cancer (AC-T)
- cyclophosphamide, adriamycin, paclitaxel
hodgkin’s lymphoma (ABVD)
- doxorubicin, bleomycin, vinblastine, dacarbazine
non-hodgkin’s lymphoma (CHOP)
- cyclophosphamide, doxorubicin, vincristine, prednisolone
common AE
- myelosuppression (leukopenia, thrombocytopenia)
- nausea, vomitting
- alopecia
- diarrhoea
