CYTOTOXIC CHEMOTHERAPY Flashcards
MOA OF DRUGS
TOPOISOMERASE INHIBITOR
(1)Stabilization /
inhibition of
enzyme/DNA
complex,
(2) Binding of Drug to
DNA totally
preventing
enzyme action,
(3) Binding of Drug
cleaves DNA in
the presence of
enzyme but
resealing by the
enzyme is
prevented.
4) Intercalation: The
planar ring structure
of anthracyclines
intercalates between
DNA strands, causing
structural distortion of
the DNA and
preventing
polymerase
progression therefore
inhibiting both DNA
and RNA synthesis
Camptothecins (Topo I) (S phase)
Camptothecin, Topotecan, Irinotecan
* acts via mechanism 1
Podophyllotoxins (Topo II) (S phase
Etoposide
* Acts via mechanism 1 or 3
Anthracyclines (Topo II) (S and M phase)
Doxorubicin
* Acts via mechanism 1, 2, 3 or 4
what metabolises irinotecan
Irinotecan is a prodrug
* SN-38 is the active metabolite
* SN-38 is inactivated by glucuronidation, the
addition of glucuronic acid by uridine
diphosphoglucyronyl transferase (UGT1A1)
what is UGT1A1
UGT1A1 is a phase II enzyme with >60 alleles
* Some alleles, eg UGT1A1*28 allele (TA)7 repeat
in TATA box of its promoter has a low activity
phenotype (
UGT1A1 is a phase II enzyme with >60 alleles
* Some alleles, eg UGT1A1*28 allele (TA)7 repeat
in TATA box of its promoter has a low activity
phenotype
Metabolism of Irinotecan
Effect of the environment
After inactivation SN-38-glucuronide is
secreted via bile into the intestines
* There it can be re-activated through
hydrolysis by an enzyme produced by gut
microflora causing severe diarrhoea.
what are common features of alkylating agents?
form covalent bonds with DNA via the production of a
reactive species.
* bivalent therefore bonds are formed across or within
stands of DNA
They are effective cytotoxics because they crosslink DNA
antimetabolites
Folate antagonists - Methotrexate
* Purine Analogues e.g. Azathioprine, 6
mercaptopurine, thioguanine
what is bleomycin?
Bleomycin refers to a family of structurally
related compounds that bind iron in the
presence of oxygen to produce a reactive
peroxide
* DNA undergoes an oxidation reaction in its
presence to induce single or double strand
breaks
* Disrupts the cell cycle in stages G2 and M
what are the two types of microtubule inhibitors
vinca alkaloids and taxanes
what are types of vinca alkaloids
Vinblastine, Vincristine
* Bind to β-tubulin to inhibit microtubule
polymerisation
what are types of taxanes
Paclitaxel and Docetaxel
* Bind to β-tubulin to stabilise the microtubule
to prevent polymerisation and
depolymerisation
