Anti Cancer Drugs Flashcards
Where did anti-cancer drugs start?
WWI mustard gas had physicians exploring why it was so toxic
What is Adjuvant Chemotherapy?
reduction in the risk of recurrence (mop up Micrometastases) given after tumour surgery.
What is Neo-adjuvant chemotherapy?
Facilitation of local resection and impact of micrometastatic disease prior to tumour treatment surgery.
What does palliative mean?
Improve the quality and quantity of life in the advanced disease setting
(curative is when someone is cured)
What are the different types of drugs used to combat cancer?
Cell cycle specific drugs
Cell cycle non-specific drugs
What are cell cycle specific drugs?
inhibit cell growth at specific phases
What are cell cycle non-specific drugs?
act on all cells independent of whether they are cycling or not
What type of agent is mustard gas?
Alkylating agent
What are alkylating agents?
Covalently transfer alkyl groups to DNA bases
How do alkylating agents work?
Alkylation of two bases results in cross bridges
cross linking prevents DNA from being separated for DNA synthesis or transcription.
not cell cycle specific as it binds to all DNA
What are the pharmacological actions of alkylating agents?
Cytotoxic actions:
interfere with DNA integrity and functions to induce cell death in rapidly proliferating tissues
Lethality of DNA alkylation depends on the recognition of the adduct
in nondividing cells, DNA damage activation depends on the presence of p53 gene.
malignant cells with mutant/absent p53 gene fail to suspend cell cycle progression
What do platinum agents do?
Bind covalently to purine DNA bases
Bifunctional intra strand cross links
Preventing DNA double strands from separating
Not S-phase specific
Binding of cisplatin to DNA is irreversible and structurally different adducts are formed.
The adducts are classified as intra-strand crosslinking of two nucleobases of single DNA strand, inter-strand crosslinking of two different strands of one DNA molecule, chelate formation through N- and O-atoms of one guanine, and DNA-protein crosslinks
Very similar to the alkylating agents
What are anti metabolites?
purine/pyrimidine analogues
How do anti metabolites work?
Act at the level of synthesis
interfere with incorporation of nucleic acids
Usually S phase specific
What are some pyrimidine antimetabolites?
5FU and capecitabine
Give an example of anti-folates?
methotraxate
What are the problems with anti metabolites?
Acts on both normal and cancer cells that are actively dividing and thus causes significant side effects e.g bone marrow and gastrointestinal toxicity
What is 5FU?
5-fluorouracil
thymidine analogue
binds to thymidylate and as a result the enzyme is inhibited and leads to reduced DNA synthesis and decreased cell proliferation
What is methotrexate?
Competitively inhibits dihydrofolate reductase
inhibits the enzymes activity for DNA synthesis and thus leads to less.
What are topoisomerase inhibitors?
Topo1 - single strand breaks
Topo2 - double strand breaks
What do topoisomerases do?
Relax supercoiled dsDNA allowing replication and RNA transcription
What do topoisomerase inhibitors do?
Topo1:
Bind to and stabilise the DNA-topoisomerase 1 adducts
Inhibits re-ligation of DNA strands and thus results in Single strand breaks in DNA which then likely mediate apoptosis
E.g Irinotecan and camptothecin
Topo2:
Forms a complex with topo2 after cleavage of DNA
Inhibits re-ligation and leaves single and double strand breaks
E. g etoposide and anthracyclines
What do Anthracyclines do?
Topoisomerase II inhibition
DNA intercalation ss and ds DNA breaks
Free radical formation binding to DNA
What is the toxicity of anthracyclines?
myelosuppression gastrointestinal alopecia local tissue damage cardiotoxicity
What are the two types of microtubule inhibitors?
Vinca Alkaloids
Taxanes
What do Vinca Alkaloids do?
stops assembly and promotes disassembly (high affinity binding to ends)
splaying and spiralling (low affinity binding to sides)
metaphase arrest, plus other cell cycle functions
toxicity - neuro, GI, marrow
What do Taxanes do?
stabilise microtubules, inhibit dynamic reorganisation
sustained metaphase / anaphase block
toxicity - neuro, marrow
What are the areas with reversible toxicities of anti-cancer drugs?
Affect rapidly dividing cells
bone marrow
GIT
Germinal epithelium
lymphoid tissue
hair follicales
What are the areas where they are irreversible toxicities?
Kidney
Nerves
Heart
Lungs
What are the assumptions of cytotoxic Chemotherapy?
Tumour growth proceeds exponentially, independent of growth homeostasis, but:
some are non-dividing cells
growth fraction may vary as a function of the tumour size
Each dose results in the same proportional log kill, but:
Proportional kill
tumours are heterogeneous
Intensity of dose influences outcome:
Cytotoxic drugs are given at close to the maximum tolerated dose
Different drugs have different kill properties
What are the aims of combination chemotherapy?
Achieve maximum cell kill with tolerable toxicity
increase kill fraction of resistant cells
prevent or slow outgrowth of resistant malignant tumours
What type of anti-cancer drug regime is most beneficial?
Sequential regimes out perform alternative regimes.
How can we personalise anti cancer medicine to patients?
Currently via randomised control trials to find a combination of drugs superior to the current ones being used.
Cannot though determine the likeliness of response in individuals
