Pharmacology 10: Cancer Chemotherapy Flashcards
characteristics of cancer cells which define the magnitude of malignant threat?
loss of cell growth control- ordered control of cell division not balanced by apoptosis
de-differentiation and loss of specific function
blood supply- tumour cells release local angiogenesis factors to promote vessel growth
metastasis and invasiveness- loss of positional sense, disruption to E-cadherin?
tumour compartmentation
which 3 compartments to tumour cells belong to?
A= dividing cells receiving adequate nutrient/vascular supply B= resting cells in G0, able to rejoin A if changes in cell signalling/local environ e.g. following surgery, more likely to be situated in middle of tumour. C= cells no longer able to divide, contribute to overall tumour bulk, present no challenge.
which compartment of tumour cells is most susceptible to chemotherapy?
A
how many cells does a tumour need to consist of to be clinically detectable or to reach size of a small grape?
10^9 cells
what is the difficulty of targeting compartment B tumour cells with chemotherapy?
proportion of chromosomal DNA in G0 open to attack is much more limited, making effective kill ratio much lower, and cells therefore available to re-enter compartment A, even following intense chemotherapy.
what is the general aim of all cytotoxic agents used in cancer chemotherapy?
drive a therapeutically higher rate of apoptotic death in cancer cells over that caused in normal cells
how do the anthracycline antibiotics work in cancer chemotherapy?
their discrete molecular ring structure enables them to intercalate between spaces between DNA base pairs, interfering with normal transcription and replication.
Antibiotic also binds to Topoisomerase II, forming a tripartitie DNA-anthracycline-Topoisomerase II complex, and topoisomerase II enables breaking, rotation and re-ligation of DNA strands in DNA replication and repair, resulting non-ligated free DNA strands act as trigger for apoptosis.
Anthracyclines can also generate free radicals by binding to Fe2+, which go on to damage DNA, which is detected by DNA damage sensing mechanisms, which trigger apoptosis.
Action non-cell cycle specific
in which phase of the cell cycle is bleomycin, a glycopeptide antibiotic, most effective?
G2
but also some effect in non-replicating G0 cells.
from which bacteria is the glycopeptide antibiotic bleomycin derived?
streptomyces fungi
how does bleomycin work to directly modify DNA structure?
binds with DNA and chelates with free Fe2+ ions
structure allows it to closely align itself within DNA by intercalation and by binding via its terminal NH2 group to DNA
reaction site when it chelates with Fe2+ then catalyses production of superoxide and OH free radical species- attack phosphodiester bonds in DNA, causing cutting of DNA strands= primary mechanism underlying cytotoxicity
what is the reactive group on alkylating agents?
electrophilic- attracts e- from nucleophilic target sites along length of DNA strands
when does the maximal effect of alkylating agents occur?
during S phase of cell cycle as DNA replicating and large sections of DNA strands exposed and unpaired
but affect cell function in all phases so cell-cycle nonspecific
examples of antimetabolites which interfere with precursors to purine and pyrimidine synthesis?
6-mercaptopurine (from azathioprine)
methotrexate
5-fluorouracil
which nucleoside has the most marked reduction in response to methotrexate?
thymidine*
enzyme inhibited by methotrexate?
dihydrofolate reductase, inhibiting production of tetrahydrofolate= methyl group carrier, co-factor
how does 5-fluorouracil act?
irreversibly inhibits thymidylate synthase
analogue of uracil= a pyrimidine base
where do antimetabolites act in the cell cycle?
specific to S phase
how do vinca alkaloids e.g. vincristine cause cell apoptosis?
inhibit microtubule formation by binding to beta-tubulin subunit, preventing microfilament formation that make up microtubule, so mitotic spindle doesn’t form and cells arrested in mitotic metaphase. chromosome cannot segregate and affected cell cannot proliferate.
how do taxanes e.g. paclitaxel and docetaxal, cause cell apoptosis?
promote and stabilise formation of tubulin polymer into microtubules, reversibly bind to beta-tubulin subunit,stopping microtubules from disassemblying so rendered non-functional, chromosome cannot be pulled apart, cell stuck in metaphase.
most common adminstration route for cancer chemotherapy agents?
IV- often their toxicity rules out oral delivery as would severely damage GI tract.
also, bioavailability often variable and ptnt likely suffer nausea and vomiting throughout tment.
IV allows fine delivery control by injected bolus, infusion bag or pump, and if emergency, infusion can immediately be stopped.
what route of delivery is used for tumours in CNS?
intrathecal and intraventricular
2 types of resistances of cancer cells to chemotherapy?
primary= resistance prior to drug exposure acquired= after drug exposure
how can acquired drug resistance come about?
multidrug resistance protein= expression may increase if cancer cells exposed to 1 or more chemotherapeutic drugs, functions to generically remove hydrophobic large xenobiotics.
may be downregulation of active carrier e.g. with methotrexate and cis-platin drugs, drug exposure decreases rate of active drug uptake
drug target enzymes may be upregulated to offset decrease in metabolite prod e.g. increase dihydrofolate reductase with methotrexate.
how can drug resistance be offset clinically?
utilise high dose, short term intermittent repeated therapy with drugs given in optimal combination.
common ADRs with cancer chemotherapeutics?
nausea
vomiting- acute phase 4 - 12 hours, delayed onset, 2 - 5 days later, chronic phase- may persist up to 14 days, action on central chemoreceptor trigger zone
diarrhoea
mucositis
alopecia
myelosuppression, impaired wound healing and skin toxicity
most frequent cause of death during chemotherapy?
haematological toxicity
why can acute renal failure occur with cancer chemotherapeutics?
rapid tumour lysis causes large increases in purines being released in to the circulation, increased purine met. generates urates which precipitate urate crystal formation in renal tubules, can then cause kidney failure and death.
=tumour lysis syndrome
why are anthracyclines especially cardiotoxic?
free radical generation
what high risk of about 10% is assoc with bleomycin?
pulmonary fibrosis
especially if patient also on O2 therapy
ADRs assoc with alkylating agents?
periperal, sensory and motor neuropathy
high frequency ototoxicity
