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drug resistant cancers
Terms in this set (15)
decreased intracellular accumulation, decreased drug activation, increased inactivation of drug or toxic intermediate, increased repair of drug induced damage, increased resistance to drug induced toxicity and drug targets altered
what are the tumour cell based mechanisms of drug resistance?
anatomic drug barriers, increased drug inactivation by normal tissues and decreased drug activation by normal tissues
what are the host dependent mechanisms of drug resistance?
a single amino acid mutation
what can affect the binding abilities of proteins?
so that it can bind and become activated
why does Hsp90 require ATP?
a molecular chaperone that assists in the folding and/or activation of client proteins
what is Hsp90?
selectively by naturally occurring antibiotics and synthetic small molecule inhibitors
how can Hsp90 be inhibited?
highly, human Hsp90 is 60% identical to budding yeast
how conserved is Hsp90?
the stabilisation of mutant overactive clients
what is Hsp90 required for?
against the many environmental stresses that cancer cells must endure and overcome
how does Hsp90 act as a buffer?
increase hydration in the vicinity of the pocket, weakening interaction
what do E88G and N92L do?
clone the BCR-ABL cDNA into plasmid encoding retroviral vector -> transform the plasmid into mutant E. coli strain -> transfer HEK293T cells with the mutagenised library for retroviral production -> library of retrovirus vector particles carrying mutagenised BCR-ABL -> transduce BaF3 cells grown in presence of IL3 with retrovirus vectors -> bulk culture or soft agar culture and the IL3 removed making the BaF3 ells now dependent on Bcr-Abl
how does resistance to Gleevec occur?
5 micro litre Gleevec -> 10 micro litre Gleevec -> isolate genomic DNA, either rescue proviruses or amplify the specific region by PCR for sequencing
what happens in bulk culture?
add Gleevec -> amplify each surviving colony separately -> isolate genomic DNA, either rescue proviruses or amplify the specific region by PCR for sequencing
what happens in soft agar culture?
reduce levels of drugs being administered to have the same effects, reduced drug levels reduces side effects and probability of cancer resistance severally reduced
what can combinational drugging do?
improve patient quality of life
what can reduced dose do?
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