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33 terms

IUSM Indy - Dudley's Antibiotic Cancer Drugs

Antibiotics, Hormonals, and Antibodies
1) T/F - daunorubicin and doxorubicin are cell cycle independent noncovalent DNA intercalators.
2) T/F - mitomycin C is a cell-cycle-dependent molecule that intercalates noncovalently.
3) T/F - bleomycin is a cell-cycle independent groove-binding antibiotic.
1) T
2) F - it is cell cycle independent, and it makes covalent bonds, much like an alkylator.
3) F - it is cell cycle dependent, and is an intercalator.
Dauno -
1) 3 mechs - what are they?
2) Admin/Metab? (an interesting story)
3) Limiting tox?
1) intercalation and breaks (maybe top II?); free radicals; apoptosis
2) IV admin; biphasic hepatic metab, and renal elim; red metabolites in urine.
3) cumulative heart tox
1) Where do they usually hit?
2) what's a bifunctional agent? What's a monofunctional?
1) They usually hit N7 of guanine; other sites are alkylated too; nitrosoureas prefer O6 on guanine.
2) A bifunctional is one that causes crosslinking; a monofunctional one is mutagenic/carcinogenic.
How does resistance happen?
(Think of doors, in, doors out, and targets).
What's a way to reverse resistance?
Less uptake, more glutathione or other inactivating agents, more DNA repair.
Can be reversed by glutathione depleters...o6 benzylquanine or ethacrynic acid.
Tox of alkylators?
1) Rapidly-dividing tissues x4
* myelosuppression/immunity
* mucosa (mouth, rest of GI)
* hair follicles = alopecia
* amenorrhea/azoospermia
2) Neuro
3) Other (pulm fibrosis, veno, renal failure, leukemia)
Nitrogen Mustards -
1) What are their names?
2) What is their mechanism?
1) mechlorethamine, cyclophosphamide, melphalan, chlorambucil. (MCMC Mustard)
2) carbonium ions form covalent bonds, and bifunx crosslinks.
Mechlorethamine = old fashioned WWI mustard gas
1) admin and metab?
2) Where does it hit, and when?
3) Toxes?
1) fast flowing IV b/c vesicant; highly reactive in H2O, and is gone in minutes!
2) N7 of guanine, and peak damage in 1st hour. DNA lesions disappear in a day!
3) The standard ones...n&v, myelo...also some reproductive problems, worse in males (sterilization), vs irregular menstruation in females.
Cyclophosphamide = stable mustard
1) Prodrug, T/F?
2) admin and metab?
3) here does it hit, and when?
4) toxes
5) How do we manage one of the main toxes of cyclophosph. (clean up the "mess")
1) T - needs liver to activate it.
2) can be oral or iv; much more stable, and can actually make it to the liver to be activated. Elimination is SLOW for a mustard - 7 hour half life.
3) Same DNA crosslinking as mechlorethamine, but more delayed - peaks in 6h.
4) all the standard ones...n&v, myelo, alopecia...AND hemorrhagic cystitis.
5) mesna helps with hemo cystitis.
Melphalan -
1) it's a mustard, but what's it stuck to?
2) Does it go thru the transporter for this molecule it's stuck on?
3) Admin?
4) Time frame?
5) toxes?
1) L-phenylalanine
2) no - uses leucine uptake instead - LOL
4) even slower DNA damage (6-12h); halflife is 1 hour, 1.5 hours or so.
5) pretty well tolerated...mostly just the hema tox.
Chlorambucil -
1) admin and kinetics?
2) Tox?
1) oral, with an hour half life (a pretty standard half life for a mustard)
2) generally just mild myelo...also gi, liver, or periods.
Alkyl Sulfonates - only one in the class.
Busulfan...a pretty bland chemo.
1) Admin/kinetics
2) Mech
3) Tox
4) What's the story about alkyl sulfonates?
1) oral, 2-3 h (so comparable to the latter 2 mustards)
2) Crosslinker - DNA/protein.
3) Myelo
4) They all have 2-9 carbon alkyl chains stuck on them...the chain can't be 6-7, though, or it loses antitumor properties.
Chlorethylnitrosoureas - Lipophilic; names end in mustine.
1) Why is their lipophilicity important?
2) how does this drug damage DNA, as well as damage the lysyls on enzymes?
3) What's the most important property?
4) tox
5) how does it activate?
1) they can slip across the BBB
2) 2 different metabolites.
3) Alkylating
4) the usual..slow myelo. also some kids get kidney problems.
5) It has to undergo decomposition to make the active carbonium.
Methylnitrosourea - a special drug for a rare tumor! (pank islet!)
1) Where's it methylated?
2) Kinetics?
3) tox
4) Is it a prodrug?
1) O6 guanine
2) short halflife...IV admin. Not a prodrug.
3) mostly n/v...
4) no.
1) Names?
2) Prodrugs?
2A) If they are prodrugs, how activated?
3) Mech and resistance?
3A) Where do they methylate?
4) tox
5) What is the name of a similar drug? Where does this drug alkylate?
1) Dacarbazine, Procarbazine
2) yes
2A) In the liver.
3) methylate DNA, cause breaks.
3A) O6 of guanine
4) Dacarbazine - myelo/n&v; Procarbazine is very carcinogenic/terato. Bad for fertility, which is relevant b/c used in young people's hodgkin.
5) Temozolomide O6, N7
1) Need activation?
2) What is the predominant adduct?
3) What is the desired result?
4) Admin - and how do they get into cells?
5) Name 2 mechanisms for resistance to platinums.
6) Which 2 platinums display cross-resistance?
7) Why is it important to maintain hydration and diuresis with a patient on platinums?
8) What are the most salient side effects of platinums?
1) Yes. Coordination chemistry with water.
2) intrastrand
3) inhibition of replication/transcription, DNA breaks and miscoding, and then activation of damage sensors (ATM kinase) and p53 and apoptosis.
4) iv; they enter cells by diffusion or by a copper pump.
5) MMR loss of function (assoc with cisplatin); NER overexpression (assoc with cis/carboplatin)
6) cisplatin and carboplatin
7) Renal damage
8) Neurotoxicities - oto, and periph neuropathy in oxaliplatin.
What is the difference between a SERM and a SERD?
A SERM is a competitive inhibitor of E binding to the E receptor, and may have agonist or antagonist effects; a SERD works more like a noncompetitive inhibitor - it binds strongly, and inhibits receptor dimerization through sterics. It leads to increased turnover of these receptors, and disrupts their ability to go to the nucleus.
1) Tell the story about tamoxifen and its metabolites.
2) What is tamoxifen used for?
3) Side effects?
4) What is used in postmenopausal women if tamoxifen fails?
1) Tamoxifen has a halflife of 7 days, but its metabolites are even more potent; these metabolites have a halflife of 14 days.
2) ER positive breast cancer, either post surg, or for mets.
3) Estrogen-related effects: atrophic vagina, hair loss, vasomotor, risk of thrombo events, nausea and vomiting; also increased risk of endometrial cancer.
4) fulvestrant
1) What drug class is fulvestrant in?
2) what is the halflife?
3) Describe the metabolism.
4) Side effects
2) 40 days!!
3) resembles steroid metabolism
4) Again, flash, headache, nausea, asthenia and pain.
1) What drug class is anastrozole in?
2) What circumstances is it used in?
3) describe its mechanism
4) side effects
1) it's an aromatase inhibitor.
2) postmenopausal women, hormone recep positive cancer.
3) binds heme of cyp 19
4) similar to tamox; fewer hemo complications (vag bleed, thrombo).
1) How do leuprolide and gosirelin affect the anterior pituitary? Why is this different from physiological GnRH?
2) What are they used for?
3) Side effects?
1) Nonpulsatile dosing of these GnRH agonists shuts down pituitary secretion of FSH and LH through feeback inhibition.
2) Palliation of hormonally responsive tumors...make sure to add things that block steroid synthesis and action.
3) loss of libido, gynecomastia, bone mass/muscle mass, weight gain...and vaso flush.
1) What does flutamide do?
2) side effects
3) is it a steroid?
4) Does it operate upstream or downstream of leuprolide?
5) Excretion?
1) blocks the AR
2) similar to gosirelin etc...loss of libido/potency, breast changes, vaso flush...also GI/liver problems.
3) no
4) Downstream. Leuprolide overstimulates the pituitary; flutamide inhibits receptors on the target tissues.
5) Urinary
1) What does Imatinib gleevec do?
2) which tumors?
3) resistance and side effects?
4) is it an antibody?
1) blocks tyrosine kinases
2) CML is the famous one - also GIST
3) mutant kinase; neutropenia/tcp in CML; n&v/edema/cramps
4) no
Gefitinib & Erlotinib ("Jeff and Earl")
1) What do they do?
2) Which cancer?
3) Tox
4) are they antibodies?
1) they block EGFR kinase.
2) non small cell lung
3) diarrhea, rash, acne (erlo - rarely, int lung dz)
4) no
Trastuzumab "HER 2 Neu Mab"
1) how do we prevent serum sickness with this one?
2) what's the mech?
3) 2 famous reactions
1) humanized
2) binds the her-2-neu receptor, inhibits growth of the cell AND promotes antibody dependent cell killing. Takes advantage of fact that some breast cancers overexpress HER2Neu
3) cardiotox, esp with doxo; hypersensitivity.
Bevacizumab - Beaver Damming Blood Vessels since 2004!
1) Mech
2) tox
1) Binds VEGF and keeps it from binding
2) hemo things - GI perf, poor healing, lung bleed. Also some nonspecifics like dizziness, diarrhea etc.
Cetuximab - "See Tux" Competition..."jeff and earl" are watching the competition from the other side of the membrane.
1) How does this one differ from Gefitinib and Erlotinib?
2) Toxes
1) "Jeff and Earl" are small kinase inhibitors; cetuximab is a competitive inhibitor and an antibody.
2) Tux is Toxic. bad infusion rxn; also lung and rash. (compare gefitinib and erlotinib)
Rituximab - "Right Tux"
1) What's the target? Result?
2) What is an infectious side effect?
3) other sides?
1) "Right Tux" hits well-dressed malignant B cell square in the CD20 cummerbund; B cell takes a bow out.
2) Hep B reactivation
3) tumor lysis; mucocutaneous, infusion
Ibritumab & Tositumab
"Burritumab & Toastumab"
1) Why are these nicknames appropriate?
1) Just like the foods, these antibodies are HOT. They carry radioactive compounds, which cook the cancers.
1) Why do they work?
2) sides?
1) they bind their receptor and initiate apopt.
2) typical cushing things - glucose, osteoporosis, immuno, psyc.
Name a drug that operates at the epigenetic level. What does it do?
Vorinostat aka SAHA (suberoyl hydroxamic acid) - inhibits HDAC.
Bortezomib "Proteasomib"
1) Remember a story from CMB about apoptosis? How does Bortezomib affect the outcome of this story?
1) Bcl-2 sends Bax to the proteasome, inhibiting apoptosis, but Bad saves Bax. WIth bortezomib, the proteasome is out of commission. Therefore promotes apopt pathways.
Name 4 general reasons a cancer might be resistant to a drug.
1) Cell kinetics - many in G0
2) Pharmacokinetics - drugs are cleared too well
3) Faulty Delivery (especially the BBB)
4) Intrinsic and acquired
Name 6 acquired mechanisms, and cite an example.
1) DNA repair - chloroethylnitrosourea, O6 guanine alkylation, and O6MGMT
2) Target site - MTX and mutant DHFR
3) Drug activation - 6MP and HGPRT
4) Drug inactivation - alkylating agents stuck to glutathione
5) Sequestration - metallothioneins disposing of cisplatin.
6) Efflux - 3 pumps -
* MDR aka P glycoprotein