Pharm 2 - Cancer 2

drraythe's version from 2015-11-09 19:08

Alkylating agents

Question Answer
What is the MOA of all Alkylating agents?Formation of a carbonium ion → instantaneous rxn w/ amine, hydroxyl or sulfhydryl groups(all part of DNA) → czs intra & inter chain cross linkinginterferes w/ transcription & replication
What is the result/way Alkylating agents are used as chemotherapeutics?Interferes w/ transcription & replication
What kinda ions do Alkylating agents form?Carbonium ion
What are the 5 major side effects of Alkylating agents?(1) Depress bone marrow
(2) GIT disturbances
(3) Sterility in men!!
(4) ↑ risk of leukemia/other malignancies
(5) Strong cross-resistance (basic (ALKyline) bitches will suck the manly virility out of you till it's just STERILITY. Shes so CANCEROUS that anyone around her is affected)
If Alkylating agents have strong cross resistance, what does this mean?Means if resistant to 1 alkylating agent, resistant to all.
What are the 5 groups of Alkylating agents?(1) Nitrogen mustards
(2) (Alkyl sulfonate)
(3) Triazenes
(4) Nitrosoureas
(5) Platinum coordination complexes
What are the 4 nitrogen mustard drugs?(1) Cyclophosphamide
(2) Melphalan
(3) Chlorambucil
(4) Ifosfamide
What is the alkyl sulfonate drug?Busulfan (ALKYLine BUS goes beep beep!)
What is the Triazine drug?Dacarbazine (TRI not to eat da CARBs)
What is the Nitrosoureas drug?Lomustine (CCNU) (You loMUST do nitros or you loMUST treat your roundcellbrain tumors or you liver loMUST perish)
What are the platinum coordination complexes drugs?Cisplatin & Carboplatin (Remember these?)
Which nitrogen mustard is a prodrug? HOW is it metabolized?Cyclophosphamide, CYP450 metabolism
Cyclophosphamide belongs to which group? What should you know about its metabolism? How is it administered? Side effects?Nitrogen Mustard. INACTIVE PRODRUG UNTIL METABOLIZED BY CYP450!! Admin oral or IV. side effects incld Alopecia, sterile hemorrhagic cystitis (the cycling isnt active till the wheels touch the ground (liver). but if you cycle till your hair falls out, you are prolly bleeding from your bladder)
***Which drug has the side effects of alopecia & sterile hemorrhagic cystitis(in bladder)? How does the SHC happen? How can you prevent the sterile hemorrhagic cystitis?Cyclophosphamide (nitrogen mustard) is the drug which czs these side effects. The SHC happens bc cyclo. is a prodrug that MUST be metabolized (CYP450) & 1 of the resulting metabolites is acrolein, which reacts w/ sulphydryl groups in the bladder. you can prevent the sterile hemorrhagic cystitis by giving the animal N-acetylcystein, bc this is a sulphydryl donor (if you CYCLE you're an ACRO-lete & you prolly have sulfury farts)
Melphalan → Which group of Alkylating agents does this belong to? admin? side effects?Nitrogen mustard group. Oral admin (IV possible), side effects are persistent BM depression; nausea & vomiting (Mel likes oral, but it makes me nauseous, Bummer (BM))
Chlorambucil → Which group of Alkylating agents does this belong to? Admin? Noteworthy attributes?Nitrogen mustard group. Oral admin. Slowest working alkylating agent - lowest chance of toxicity (CHLORine gas & MUSTARD gas. drinking a little chlorine wont hurt you.....What are you slow?)
Which alkylating agent has the lowest tox & why?Chlorambucil & it has the lowest tox bc it is the slowest working
Lomustine → Which group of Alkylating agents does this belong to? admin? What should you know about its metabolism? How widely used is it?Nitrosourea alkylating agent, ORAL admin, metabolized into active metabolites in the LIVER, but there is limited info on it in vet med. (loMUST inhale the NITRO through your MOUTH, but loMUST be careful of your LIVER)
Lomustine → for what cancers do you use this drug? What are the side effects?Nitrosureas. Used in relapse canine lymphoma, brain tumors, epitheliotropic cutaneous lymphoma, mast cell tumors. Major side effect is that it czs hepatotoxicity in dogs (makes sense, since it's metabolized into active metabolites IN the liver) (lymphomas & Mast cell tumors are both discrete cell & then BRAIN CRAP, so, you loMUST treat these fast! but you loMUST watch your liver!)
Dacarbazine → What group does this drug go under? What should you know about its metabolism? What cancer is it used to treat? What can you combine it with?Triazene & it is metabolized into active metabolites in the liver. it is used in refractory lymphoma combined w/ Doxorubicin(cytotoxic agent) (TRI not to eat da CARBs, if you do, be ACTIVE to METABOLIZE, so you can run w/ your dog (a DOXie). This regiment might get rid of your REFRACTORY fat...or lymphomas)

Cytotoxic ABx & L-asparaginase

Question Answer
How do cytotoxic ABx produce their effects?Mainly through direct interaction w/ DNA
What should you NEVER use cytotoxic ABx with?Do not use together w/ radiotherapy (toxicity) (bad talk about ABX on the RADIO)
Doxorubicin & the anthracyclines (& Mitoxantrone) → How do these work? What is Mitoxantrone, exactly?Inhibits DNA (Topoisomerase II) & RNA synthesis. Mitoxantrone is substitute for Doxorubicin, bc Doxorubicin has a high risk of cardiotox & Mito. doesnt. (DoX & mitoX both have x's, so, can substitute each other. all cytotox ABx (hence -cin, -cycline) & thus interfere w/ DNA/RNA synth)
Dactinomycin → How does this work?Intercalates in DNA interfering w/ RNA polymerase & Topoisomerase II (Dac made of tin is just interfering w/ the dank riverbank of the TOPO river)
Bleomycin → How does this work?Fragmentation of DNA chains...(It’s a frag bomb, it goes BLEOM!) It also acts on non-dividing cells
(remember -mycin is ABx, so, know its a cytotox. ABx, in this case it o-BLEO-terates everything, inclding healthy cells)
Mitomycin → What should you know about this?(Cytotoxic ABx) Activates to give an alkylating metabolite! (remember: Mito was a basic cis boy, but we bonded anyway)
(Basic) MOA of L-asparaginase?Deaminates asparagine, inhibiting protein synthesis
(Steps) MOA of L-asparaginase?Catalyzes hydrolysis of L-asparagine to L-aspartic acid & ammonia → Depletion of extracellular stores of L-asparagine → inhibition of protein synthesis (Tumor cells can resist if they can make their own L-asparagine)
What is the limitation of using L-asparaginase as a chemotherapeutic agent?It only works in tumors which LACK L-asparagine synthetase (bc if they have this enzyme, they can make their own asparagine, so you can't deplete it)
What are the side effects of L-asparaginase?Hypersensitivity rxns & pancreatitis (allergic to asparagus & why would you give it to your dog anyway, will proly cz pancreatitis)

Plant derivatives

Question Answer
What is the MOA of Vinca alkaloids?Drugs bind to tubulin & inhibit its polymerization into microtubules → Prevent spindle formation in dividing cells - arrest cell at the metaphase
How safe are Vinca alkaloids?Relatively safe
What are the side effects of Vinca alkaloids?Mild myelosuppression
Paresthesia (sensory changes)
Muscle weakness
(Relatively safe drugs) (Hanging out w/ Vin is interesting - I feel strange & weak. Definitely suppressed)
Where do Vinca alkaloids come from (which plant)? What are the 3 active substances?Come from Madagascar Periwinkle (Vinca Winka)

What is the MOA of Taxanes?They stabilize the microtubules in the polymerized state (so no cell division occurs), cell arrests at metaphase
What are the 2 Taxanes? How do you admin them?Paclitaxel (IV) (Has an I in it)
Docetaxel (PO) (Has an O in it)
(PAC your blood full of plants & then eat a DOCE to get yew mind off of TAX day)
Where do Taxanes come from? (plant)The Taxus sp. from the BARK OF THE YEW TREE (Tax Tree)
What are the side effects of the Taxanes?Serious bone marrow depression & cumulative neurotoxicity. Paclitaxel (pacman is very sensitive) may cz hypersensitivity. DO NOT USE IN HORSES, VERY TOXIC!! (High taxes on Horses, they are expensive. They TAX me to the BONE, it makes my BRAIN hurt. OR Its a TAX on the BONES & BRAINS! Good thing you dont need brains to bone, har har)
Which plant derivative do you not use in horses?Dont use the Taxanes (Paclitaxel & Docetaxel) in horses (Horses are expensive, expect to pay a lot of sales TAX)

Tyrosine kinase inhibitors, Monoclonal Antibodies & Selective Inhibitors of Nuclear Transport (SINTs)

Know where Tyrosine kinase inhibitors act!!
Question Answer
(Basic) MOA of Tyrosine kinase inhibitors?Block activity of downstream signalling or receptors
(Steps) MOA of Tyrosine kinase inhibitors?In cell, block downstream signaling of growth promoters or block receptors (STUDY GUIDE SAYS: Inhibit angiogenesis or cz dysregulation of cell growth: inhibit downstream signaling) (Tyro signaled Kinny downstream to stop Angie)
What are the 3 Tyrosine kinase inhibitors he mentions?Imatinib
(Group?) What is Imatinib used to tx? in who?(Tyrosine kinase inhibitor) Mast cell tumors & Sarcomas in dogs & cats (IM an equal opportunity lover of both cats & dogs - I MAST SARcome to their adorableness)
(Group?) What is Toceranib used to tx? In who?(Tyrosine kinase inhibitor)
Mast cell tumors
Myeloma in dogs
(Tocer is a KINd dog made of Mast cells, Sarcoma/Carcinoma, Melanoma/Myeloma)
(Group?) What is Masitinib used to tx? In who?(Tyrosine kinase inhibitors) Mast cell tumors in dogs
MOA of Monoclonal Abs?Block specific receptors, so you need to make sure these receptors are expressed in the tumor you are trying to target in order for an effect
Cetuximab is used to tx?ErbB-1 expressing tumors (C #1) (OR C is the 1st letter after B)
Trastuzumab is used to treat?ErbB-2 expressing tumors (T comes after C & T for 2)
Bevacizumab is used to treat?VEGFR (receptor) in Mastocytoma cells (put VEG in your BEVer if you dont have a MAST) (WTF? .....I dunno, just go w/ it)
Lifehack on remembering the Tyrosine kinase inhibitors & the Monoclonal Abs?All the Monoclonal Abs end in MAB (Monoclonal Anti Body) & all the Tyrosine kinase inhibitors end in "nib" which are some of the letters in inhibit
What is Exportin-1 (XPO-1)? How does it relate to "Selective Inhibitors of Nuclear Transporters (SINTs)"?Exportin-1 is a protein that transports growth regulator proteins & tumor suppressor genes out of the nucleus, inhibiting apoptosis. Exportin-1 is upregulated in many cancers. (SO WE WANT TO INHIBIT XPO-1 to PROMOTE apoptosis)(so if you inhibit the transporter czing more growth regulators, tumor suppressors & apoptosis promoters to accumulate in the cell. The tumor cells are more likely to be regulated/suppressed/apoptosed)
(Werner's notes are wrong, here is the article proving so
What are the 2 drugs that are Selective Inhibitors of Nuclear Transporters (SINTs)?Selinexor & Verdinexor (NEXOR SELECTS-OR)

Steroid hormones & antagonists

Question Answer
What are the things glucocorticoids do?Direct destruction of tumor cells, ↓ tumor size & help in management of secondary complications
What are the side effects of glucocorticoids?They induce PgP expression (PgP transports drugs out of cells) Which means they might induce multi-drug resistance (resistance isn't futile - it's sweet)
***Anti-androgens → What is the drug? When are these useful? When are these NOT useful?Delmadinone
Useful in Peri-anal gland tumors as replacement for castration. NOT useful in Prostatic Carcinomas though (turn that MadMan into a madin (maiden) bc that's better than tumors around your anus)
Delmadinone is a what?Anti-androgen (MadMen)
Anti-estrogens → What is the drug? When/how is this used?Tamoxifen → Selectively inhibits estrogen receptors. Dog & cat mammary Carcinomas have ↓ numbers of estrogen receptors (estrogen & progest stuff for mammary. TAM was not super femme, but she was amazing & would punch your breasts right off. Also the word looks like "tamponxifen")
Tamoxifen is a what?Anti-estrogen which selectively inhibits estrogen receptors
Anti-prostagens might be used for what?Might be useful in some mammary tumors (prostaglandins & boobs & stuff)


Question Answer
What are the 2 basic types of resistance?Primary or Acquired (adaptation or mutation)
↓ accumulation of cytotoxic drugs is done by tumors how?↑ expression of drug transport proteins on the cell surface
What are the drugs which are resisted by ↑ expression of drug export proteins on the cell surface?Doxorubucin
(Vin the doxie blasted off the tin dac as he was exported from the house)
Which drug is resisted bc of ↓ uptake of the drug by the cell?Methotrexate
Resistance may be gained by insufficient activation of the drug → What is a situation & a drug where this happens?Failing metabolic activation of 5-fluorouracil
↑ utilization of alternative metabolic pathways allows resistance to what drugs?Antimetabolites
Rapid repair of drug induced lesions is how tumors gain resistance to what drugs?Alkylating agents
Altered activity of the target (in this case, of Topoisomerase II) is how tumors gain resistance to what drug?Doxorubicin