anthracyclines Flashcards
what are the classes that fall under antitumor antibiotics
anthracyclines: doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone
chromomycins: actinomycin D, plicamycin
miscellaneous: bleomycin, mitomycin
3 mechanisms of anthracyclines
- DNA intercalation
- free radical generation
- inhibit topoisomerase (Topo2A)
what is the main adverse effect of anthracyclines
cardiotoxicity
Topo I vs Topo II
Topo I: creates a SINGLE BREAK in DNA and passes a second strand or duplex through the break
Topo II: cuts both strands of the DNA helix simultaneously in order to manage DNA tangles and supercoils
what happens after Topo II cuts both strands of the DNA helix
the ends of the DNA are separated–> a second DNA duplex is passed through the break–> following passage, the cut DNA is re-ligated
2 isoforms of Topo II
Type IIA: expressed in proliferating cells
Type IIB: expressed more widely (including cardiomyocytes– cardiotoxicity)
describe how the anthracycline MOA requires intercalation
the planar aromatic/heteroaromatic ring systems slide between the base pairs of the DNA double helix–> which causes structural & functional DNA changes
describe how the structure of anthracyclines is important for their intercalation
presence of a positively charged amino sugar as the carbohydrate moiety attached directly to the anthracyclinone: plays a critical role in intercalation by forming an ionic bond with the negatively charged phosphate groups of the DNA backbone
describe how free radical generation is critical for the mechanism of anthracyclines
reactive oxygen species generated by anthracyclines induce oxidative stress & DNA damage.
ROS-mediated toxicity involving activation of NF-kB has been demonstrated for endothelial cells. NF-kB activation in cancer cells blocks apoptotic cell death: different mechanism for toxicity vs efficacy
describe how Topo inhibition is important for anthracyclines mechanism
related to the poisoning of topoisomerase II: subsequent Topo2A poison-mediated cytotoxicity is postulated to involve the mismatch repair genes (MSH2, MLH1). when repair fails: cell death is initiated
loss of DNA mismatch repair function results in resistance to doxorubicin
how are anthracyclines different from topoisomerase inhibitors?
- the topoisomerase inhibitors bind DIRECTLY to DNA-topo complex, while anthracyclines INTERCALATE.
- topoisomerase inhibitors are cell cycle DEPENDENT. anthracyclines are cell cycle INDEPENDENT.
- anthracyclines cause accumulation of reactive oxygen species (ROS)
3 main metabolic routes of anthracycline metabolism
- two-electron reduction
- one-electron reduction
- deglycosidation (hydrolytic or reductive)
varying amounts of anthracyclines may be eliminated from the body unchanged
how is cardiotoxicity with anthracyclines defined
new-onset heart failure and/or detection of left ventricular dysfunction in exposed individuals
prior to treatment: comprehensive assessment & echo.
if symptoms develop: echo for workup
the risk of anthracycline-induced cardiotoxicity is______
dose-dependent
mechanism for anthracycline-induced cardiotoxicity
controversial with several hypotheses:
-further reactions of ROS with iron. three features: myocyte death, ROS generation, dysfunctional mitochondria
-inhibition of topo2β, the main topo isoform in mitochondria
