Principles of selective Toxicity Flashcards
What criteria must be met to target cells with therapeutic agents?
- difference between the biochemistry of host tissues (body tissue) and infectious agents (microbes)
- difference between normal and cancer cells
- drugs being used must have a high degree of discrimination
(high ratio of effects to toxic effects)
What does a cell need in order to become cancerous?
mutation
alterations
What are the hallmarks of cancer?
- sustained proliferative signalling (signals to divide shouldnt stop)
- cells resist cell death
- cess should be able to induce angiogenesis (a blood supply to itself)
- cell must be able to evade chemicals that suppress growth
- cell must be able to activate invasion and metastasis
What are the aims of cancer therapy?
eradicate the disease
induce remission (period where disease is gone, but it does come back)
control the symptoms of cancer
Cancer therapy is selective. What does this mean?
mainly only selective to cancer cells bc= high cell division rate
to achieve this selectivity= look at cellular, biochemical and molecular differences between cancer cells and healthy cells
Why are drugs combined?
to reduce dosage of a single drug (that could cause side effects)
What is a problem with drug combination?
can lead to drug drug interactions
cause side effects
this can reduce patient compliance
What is the criteria to combine drugs?
- drugs that are combined must be active when used alone
- the drugs that are combined must all have different mechanisms of action
- the drugs that are combined must have different toxicity profiles
- the drug doses should be close to their maximum tolerated levels
What considerations need to be taken into account when using chemotherapy?
drug require hepatic metabolite activation?
patient nil by mouth?
Which drug needs hepatic metabolite activation?
- cyclophophamide needs p450 enzyme activation
- drug needs to be metabolized to phosphoramide mustard which is the active agent
What is a nanoparticle delivery system?
deliver drug to cancer cells without being toxic to body cells
What do you have to think about with nanoparticly delivery?
- drug cannot be released or degraded prematurely
- must have a stable structure that can effectively and efficiently deliver the drug
What is a side effect of combination therapy?
myelosuppression (bone marrow is suppressed)
What do cytotoxic drugs do?
kill cells
- active against cycling/proliferating cells (cells that are quickly proliferating and dividing)
Where do cytotoxic drugs act?
- drugs may be phase specific (affect certain parts of the cell cycle)
- drugs may be cycle specific (affect cells cycling throughout the cell cycle)
- drugs may affect DNA synthesis
What do cancer drugs not affect?
have less activity on non-dividing cells
in G0 phase (most of normal body cells)
Where are the checkpoints of the cell cycle?
- between G1 and S
2. between S and G2
What is an example of an alkylating agent for cancer therapy?
cycle specific
attack cell throughout cell cycle
e.g.
cisplatin
What does cisplatin form?
highly reactive carbonium ions (C+)
What do carbonium ions do?
transfer alkyle groups to nucleophilic sites on the DNA by covalent bonding
The movement of alkyle groups causes what on cells?
DNA cross linking
abnormal base pairing
DNA strand breakages
RNA and protein damage
these: reduce the capacity of the cell to make proteins, and if the cell cannot make proteins, it will die
What is the therapeutic index of cancer drugs?
normally at best= 1
- the conc of druf that causes toxicity=the conce of druf that causes cancer cell death
wider the therapeutic index of a drug, the better
Why do cancer drugs cause side effects?
bc it targets dividing cells
and most of the body cells are dividing
but there is selectivity for fast dividing cells (tumours)
What do cancer cells need to grow for DNA metabolism?
cofactors
provided by folic acid
What is folic acid needed for?
DNA metabolism
all cells need it but bc cancer cells divide faster, they need more
What is the folate pathway?
humans usually get folic acid from the diet
however some cancer cells can produce their own folic acid with the help of enzymes such as dihydropteroate synthetase and dihydrofolate reductase (no need to know enzymes)
DIET—-(DIHYDROPTEROATE SYNTHETASE)—DIHYDROFOLIC ACID—-(DIHYDROFOLATE REDUCTASE)—-TETRAHYDROFOLIC ACID—FOLIC ACID
What is methotrexate?
folic acid analogue
binds to catalytic site of DIHYDROFOLATE REDUCTASE and inhibits it
so folic acid not made
What happens if there is no folic acid made?
affects DNA synth and protein synth
What do you need to take into account before prescribing antibiotics?
- identify the organism responsible for symptoms
- check illness severity
- see if patient had antibiotics course before
- check for allergies
- check for other medications and any possible interactions
Why do you need to check if the patient is on OCP before prescribing antibiotics?
antibiotics can cause contraceptive failure
What do antibiotics target in bacteria?
- synthesis of peptidoglycan
- protein synthesis in the bacteria
- folate metabolism
- DNA,RNA, Cell membrane synthesis
What is the bacterial cell wall made up of?
peptidoglycan
What is peptidoglycan made of?
- sugars and amino acids =semi rigid
- polysaccharide part made of NAG and NAM-these act as long poles
- the protein portion is made up of short chains of amino acids that link the NAG and NAM together making a mesh
- the peptidoglycan also has lipopolysaccharide which is a major component of gram negative bacteria
Where are NAG and NAM made and how are they transported?
- made in the cytoplasm
- transported by bactoprenol into cell wall if cell needs to make a new cell wall
What is the lipolysaccharide made of?
lipid A and polysaccharide portion
What is lipid A and what does it cause?
ENDOTOXIN
causes fevers
What is transpeptidase?
enzyme for cell wall synthesis
forms peptide bridges- cross links NAG and NAM
- connects each row of sugars with its adjacent row
- connects each layer of peptidoglycan with its adjacent layer
- forms tight knit structure of the cell wall
What is the chemical name for penicillin?
benzylpenicillin
What does penicillin have?
beta lactam ring
it is bacteriacidal
What does the beta lactam ring do?
acts on transpeptidase
blocks enzyme
What are aminoglycoside antibiotics?
antibiotics
inhibit protein synthesis
e.g. gentamicin, streptomycin etc
How do aminoglycoside antibiotics work?
targets on ribosomal machinery (bacteria have 70s ribosomes)
How do the aminoglycoside antibiotics, streptomycin and gentamycin work?= FOCUS ON THIS QUESTIONS DONT ACC NEED TO KNOW THE OTHER ANTIBIOTICS FOR THIS
30s portion = changes its shape= leads to the reading of the mRNA code to be incorrect
How does the aminoglycoside antibiotic, chloramphenicol work?
chloramphenicol = 50s portion = inhibits formation of peptide bonds between amino acids
How does the aminoglycoside antibiotic, tetracycline work?
tetracycline interferes with tRNA attachment
How does the aminoglycoside antibiotic, erythromycin work?
erythromycin = 50s portion = prevents translocation−so ribosome cant move along mRNA
What type of organisms are fungi?
eukaryotic
live as saprophytes (live on and get food drom dead decaying matter) or parasites
What is a fungal infection called?
mycoses
can be superficial (hair, nails)
or systemic (organ, tissue)
What are the 3 main groups of fungi that can case disease in humans?
- moulds = cause athletes foot and ringworm (an infection of the skin)
- true yeasts = can cause cryptococcal meningitis and lung infections in immuno-compromised individuals
- yeast like fungi - can cause oral and vaginal thrush and septicaemia
What are polyene macrolides?
group of antifungal agents
act on cell membrane of fungus
e.g. amphotericin B (which is lipophilic and is used for very serious life threatening infections like candidal infections) and nyastatin (used for oral and vaginal thrush)
How does Aphotericin B work?
- it interacts hydrophobically with the ergosterol in fungal cell membrane
- forms a pore within it
- cause electrolyte leak out
- amphotericin B binds strongly with ergosterol- creates transmembrane channel and the cell contents (electrolytes) leak out
When someone is infected with HIV, what does the virus attach to?
CD4 and CCR5 receptors on human cells
allows virus to enter cell
What type of virus is HIV?
RNA
RNA needs to be converted to DNA (by enzyme reverse transcriptase)
What is zidovudine?
nucleoside analogue inhibitor= stops RNA converted to DNA
What kind of a drug is zidovudine?
- thymidine analogue
- has azido N3 group instead of OH group
- prodrug (need to phosphorylate) to active metabolite zidovudine triphosphate
- zidovudine triphosphate (HAS HIGHER AFFINITY) competes with endogenous thymidine triphosphate for reverse transcriptase enzyme
- zidovudine triphosphate is added to DNA being made by reverse transcriptase, the DNA synthesis is terminated (chain termination)= BC of lack of the OH group in zidovudine
When a mosquito bites a human, what does it release?
sporozoites
affect parenchymal cells of the liver
What do sporozoites do?
either stay dormant and activate within a few years
OR
mature in hepatocytes and form schizonts
What can some schizonts do?
- leave this continuous cycle in the blood cells (remain in blood cells but do not cycle as normal)
- form gametocytes (male and female gametes) through sexual reproduction
- When the person gets another mosquito bite, the mosquito takes these gametocytes
- the male and female gametes combine, form a 2n zygote and mature in the mosquito to form ookinete in the mosquito midgut
How do antifolate drugs work IN PARASITES?
competition with substrates to bind enzymes required in the synthesis of folic acid
put themselves in folate pathway
form pseudofolate
does not function like the real folate
where do antifolate drugs work in parasites?
these drugs act on DHFR in parasites
−methotrexate targets here too for cancer
- high doses of antifolates used for parasites may inhibit host DHFR
Give an example of antifolate?
proguanil
What does proguanil do?
- selective inhibitor of plasmodial DHFR (parasitic DHFR) and thymidylate synthase (thymidylate synthase imp for DNA synth)
- prodrug and thus needs to be activated
−it is converted to an active triazine metabolite in the body (cycloguanil)
How do bacteria make their own folic acid?
PABA
pteridine
What is sulphonamide?
antifolate
compete with PABA bc similar structure to bind to dihyropteroate
How does sulphonamide work?
- sulphonamide compete with PABA
- complex between sulphonamide and pteridine form
- cant go through rest of pathway
- cant bing to glutamate to become folic acid
