Block 6 - German Lectures Flashcards
Which phase of cancer is the last one that is reversible with diet and lifestyle changes?
Promotion
What are the 3 classifications of anti-cancer drugs?
Immunotherapy
Chemotherapy
Hormonal therapy
Drugs that are directed against tumor DNA have 3 different MOAs. List them and give an example.
- break the helix itself (cross-linkers)
- interfere with DNA-related proteins (topoisomerase inhibitors)
- modify the expression of genes (alkylating and methylating agents)
Which form of cross-linking can be easily removed?
Intrastrand (on the same strand)
The common site of attack for DNA cross linking is
the 7-position N of guanine
What much DNA alkylating agents contain (structurally speaking)?
must have electrophilic centers with good leaving groups
- the general structure is an R group with the central molecule (electrophile) attached to two leaving groups
Why do alkylating agents cause toxicity?
They are non-selective for cancer cells and will attack all rapidly dividing cells (like the skin)
What issue arises with the use of ifosfamide?
It is a prodrug with two different isomers (S and R).
The S isomer is responsible for the formation of the actual alkylating agent (aziridine)
The R form causes nephrotoxicity because it can be converted to chloroacetaldehyde in the nephrons.
What is the actual alkylating agent made from the prodrug ifosfamide?
Aziridine
Which alkylating agent’s toxicity can be treated using an adjunct therapy of mesna?
Cyclophosphamide. It’s main toxicity comes from acrolein and CAA.
Acrolein can be counted with mesna because mesna (injected in the active form and selectively reduced in the kidney) will concentrate in the bladder and scavenge acrolein.
What are the important points to remember about platinum compounds?
- Platinum is electron deficient
- must be stabilized by amino acids to prevent it from reacting with everything
- NH3 act as stabilizing groups and chloride ions make for good leaving groups
- when it cross-links the DNA in the cis configuration it cannot be repaired by the cells
- side effects include nephrotoxicity, emetogenesis, and neurotoxicity (limiting factor in use)
Which drugs are intercalting agents?
anthracycline
etoposide (topo 2 inhibitor)
irinotecan (topo 1 inhibitor)
topotecan (topo 1 inhibitor)
Which drugs are S phase specific?
Topoisomerase inhibitors (specificaly topo 1) DNA chain terminators
Note - topo 2 inhibitors can act during early G2
Why do irinotecan and topotecan have basic side chains on C10 and C9, respectively?
To increase water solubility
What side effect is characteristic of all intercalating agents?
Myelosuppression
What is unique about teniposide (a topo 2 inhibitor) that makes it more potent than other drugs of its class?
it has a tienyl moiety (sulfur) that increases its lipophilicity, thus increasing its uptake and potency
Which kind of topoisomerase inhibitor is able to bind to either the topo-DNA complex or the topoisomerase itself?
Topoisomerase 2 inhibitors
Which topoisomerase 1 inhibitor causes diarrhea?
Irinotecan
What must all intercalators have in their structure?
Need large (usually multiple rings) planar (flat) surfaces so they can fit between pairs of DNA
Why are anthracyclines called antitumor antibiotics?
Because they’re isolated from microorganisms and used to treat cancer.
Which stage of the cell cycle are anthracyclines specific to?
G2
How do anthracyclines cause cardiotoxicity? How can it be mitigated?
They form superoxide radicals and hydroxide radicals.
The hydroxide radicals are formed through the Fenton reaction, and cardiac tissues don’t have enough catalases or cytoprotective enzymes.
The solution is to co-administer an antioxidant and an iron chelator.
Why do anthracyclines have “rubicin” as the suffic?
They turn urine red.
What makes epirubicin less toxic than doxorubicin?
The 4’-hydroxy group on epirubicin is in the beta position and thus less prone to one-electron oxidation
