Pharm 2 - Cancer 1

drraythe's version from 2015-11-09 18:43

Intro, Tumorigenesis, complications of Chemo & Combo Therapy

Question Answer
What is cancer?Cancer is an uncontrollable multiplication (from abnormal regulation of cell division & tissue growth) & spread of abnormal forms of the body’s own cells
What is a major complication w/ anti-cancer meds?Host cell toxicity w/ cancer mediation
What are the interventions for cancer (between 2 big choices)Medical vs. surgical intervention
What are 2 genetic/epigenic(relating to or arising from nongenetic influences on gene expression) czs of cancer formation?(1) Inactivation of tumor suppressor genes
(2) Activation of oncogenes (mutation of normal genes)
Uncontrolled proliferation is czd by what 3 things? (not gene stuff)(1) Growth factors &/or their receptors (we can try to antagonize these)
(2) Intracellular signaling pathways (tumors inhibit apoptosis)
(3) Telomerase expression
How are vessels affected by tumors? What do we think we can do about this?Tumors can cz angiogenesis (since it needs O2 & energy to grow), but we can slow down or inhibit this angiogenesis w/ NSAIDS
What are the 5 characteristics of cancer cells?(1) Uncontrolled proliferation &/or escape from normal regulation of cell division & tissue growth (resistance to apoptosis (NSAIDs) - Telomerase expression)
(2) Dedifferentiation & loss of fxn
(3) Angiogenesis
(4) Invasiveness
(5) Metastasis
What are the 4 categories of complications of chemotherapy?(1) Extravasation of the drug
(2) Anaphylactic rxns
(3) Toxic side effects
(4) Acute Tumor Lysis Syndrome
A Type-1 acute hypersensitivity rxn to chemotherapy can happen from what 2 drugs?Doxorubicin
Explain the differences of location of hypersensitivity rxns (remember which drugs usually cz hypersensitivity rxns) in dogs vs cats(Doxorubicin or L-asparaginase)
Dog is usually cutaneous & GIT
Cat is usually respiratory
(Dogs always get skin problems! & also of course the bigger animal barfs. & cats not breathing? Think of the resp video of the cat w/asthma, say, bc of allergies bc this is hypersensitivities)
What are the 2 main toxic side effects (which systems) of chemotherapy & why is this?GIT & BM depression
Chemotherapeutics usually target rapidly dividing cells → Where in the body are there usually rapidly dividing cells? GIT & BONE MARROW!!
Describe what happens in bone marrow toxicityUsually develop leukopenia since the t1/2 of a leukocyte is usually just a few hours (chemo attacks rapidly dividing cells)
anemia is a fairly rare symptom bc the t1/2 of a RBC is ~120d
Describe what happens in GI toxicityDirect stimulation (of the CTZ?) will cz anorexia & vomiting. Also diarrhea can be czd by some specific drugs (Doxorubicin, Methotrexate, Vincristine). There are also breed susceptibilities (Scottish shepherd, Bobtail, West Highland Terrier)
What are the chemo drugs which are known to cz diarrhea?Doxorubicin
(If Christ's doxy takes meth, he's gonna shit everywhere OR diarrhea DVM)
What are the breeds most susceptible to GIT toxicities?Scottish shepherd
West Highland Terrier
(BOB had a SCOTch in the WEST HIGHLANDS & it made his stomach upset)
What situation would cz a much higher risk of toxicities w/ chemotherapeutics? Which drugs are the primary exacerbaters of this problem?If the animal has a mutation in the MDR1 transporter (IT IS A P-GLYCOPROTEIN). The transporter isn't there/doesn't work, so drug stays in system longer & czs MORE bone marrow & GIT toxicities than usual. The drugs which usually are transported by the MDR1 transporter (& thus exacerbate the prob) are:

(Medical DRs have dumb names for their Doxies like VinVin)
Mutations in the MDR1 P-glycoprotein transporter mean the animal will have more toxicities associated w/ what 3 drugs?Doxorubicin
(Medical Drs have dumb names for DOXies like VinVin)
Acute Tumor Lysis Syndrome → What czs this? What has a higher risk of making this happen? What happens (clinpath wise)? CS?Happens if there is RAPID tumor lysis. It is esp. seen in malignant lymphoma(makes sense, since it's in a major highway in the body) after chemo/radiotherapy.
It leads to:
High Uric Acid conc
Metabolic acidosis

(stuff from inside cells released, products of cell destruction)
CS incld:
Mental depression
***What are 2 reasons you'd want to use combinations of chemotherapeutics, as opposed to a single one?(1) ↑ cytotoxicity w/o necessarily ↑ general toxicity (attack tumor in diff ways, so don't need super high dose of any 1 thing)
(2) ↓ the possibility of the development of resistance to individual agents
How often do you dose chemotherapeutics & why?Given in 2-3 week intervals to permit the bone marrow to regenerate
Would you want to break up chemotherapeutics into small doses, or give in a few big doses?Same dose of an agent is more effective when given in 1 or 2 large doses, in contrast to giving a bunch of smaller doses (bigger is better, in this case)


Question Answer
What are the 5 groups of chemotherapeutic agents?Cytotoxic drugs
Hormones (Steroids
Monoclonal Antibodies (MABs)
Protein kinase inhibitors (NIBs)
What are the 4 groups of cytotoxic drugs?(1) Alkylating drugs
(2) Antimetabolites
(3) Cytotoxic ABx
(4) Plant derivatives
Alkylating drugs are under what category of chemotherapeutic drugs? How do they work?CYTOTOXIC drugs. They form covalent bonds w/ DNA, hence impede replication
Antimetabolites are under what category of chemotherapeutic drugs? How do they work?CYTOTOXIC drugs. They block or subvert 1 or more metabolic pathways involved in DNA synthesis (Cells can resist these drugs by upping their metabolism or choosing a diff pathway)
How do Cytotoxic ABx work as chemotherapeutic drugs?They are substances of microbial origin that block mammalian cell division
Plant derivatives can be used as chemotherapeutic drugs how? (What category of drugs do they fall under?)(CYTOTOXIC drugs) Some Plant derivatives specifically impede microtubule fxn & hence formation of mitotic spindle (MICRO-FLORA. get it?)
Hormone chemotherapeutics → Which hormone specifically is useful? Explain how it worksSteroids are the most important - drugs that suppress hormone secretion & antagonize hormone action
When do you use Monoclonal Abs as chemotherapeutic agents?Useful when fighting a SPECIFIC type of cancer
Protein kinase inhibitors → How do they work/why are they used as chemotherapeutic agents/ what makes these nice?Inhibition of Tyrosine kinases that transduce (pass on) growth signals in rapidly dividing cells (& it is restricted to only rapidly diving cells) (so stop the Tyrosine kinase that is making growth signals happen in ONLY rapidly dividing cells)

Classification Chart

Question Answer
Which drug inhibits Dihydrofolate (DHF) reduction, block DTMP & purine synthesis?Methotrexate (it is an antimetabolite of folate!) (It doesn't matter if you take your FOLATE when you're preg, if you're taking METH too, then your babies DNA is going to be screwed up)
Which drug blocks Topoisomerase fxn?Doxorubicin (DOXies biting TOPs bc theyre spinning around)
Which drugs block activity or receptors?Tyrosine kinase inhibitors (NIBs)
Monoclonal Abs (MABs)
Which drug inhibits DTMP synthesis?5-fluorouracil (5 w/ a FLU is a DirtyTrampMostlyPolluting) (ALSO SHOULD SAY BLOCKS THYMDALATE SYNTHASE, BC IS ANTIMETABOLITE)
Which drugs form adducts (DNA adduct is a piece of DNA covalently bonded to a chemical) w/ DNA?Alkylating agents
(MITO was a ALKAline CIS boy, but we BONDED anyway)
Which drug deaminates Asparagine → Inhibits protein synthesis?L-asparaginase (czs anaphylasis & pancreatits)
Which drugs inhibit fxn of microtubules?Paclitaxel
Vinca alkaloids

(MICROscopic PACman named Vincent wont pay his TAXes)
(these are all the Plant derivatives)

BCG+Cisplatin & Carboplatin

Question Answer
What does BCG stand for? (What is it?)Live whole cell Bacille Calmetter-Guerin (It's actually a vx!)
How does the BCG work (why would we use it?)Stimulates the immune system to recognize specific antigens of tumor cells
What does BCG enhance?Enhances tumor cell destruction
Which cancers is BCG usually used to tx?Usually used to tx Squamous Cell Carcinomas & Sarcoids (things youd see on a horse's face)
How many doses of BCG do you usually give?Repeated injxns until complete regression
What are the side effects of BCG? How can you try to avoid this side effects?Local & systemic anaphylaxis (pre-treatment w/ glucocorticoids to try to overcome anaphylaxis) (vaccine allergies? or just allergic to French names? put some sugar on it, baby)
What is the MOA of Cisplatin & Carboplatin?Analogous to Alkylating drugs (form covalent bonds w/ DNA, hence impede replication). So the drug enters the cell → The Cl- (of the drug) disassociates, which forms a reactive complex → the reactive complex czs intrastrand crosslinking of DNA → czs local denaturation of DNA
What are the side effects of Cisplatin & Carboplatin?NEPHROTOXIC, nausea & vomiting (platinum kidneys aren't good for you!)
What is a benefit of using Cisplatin & Carboplatin?It has low myelotoxicity which means the bone marrow is preserved/spared (having platinum kidneys is bad, but your bones (marrow) Will BE as strong as platinum)
What is Oxaliplatin?A safer version of Cisplatin & Carboplatin used in human med (not yet avail for animals)

Antimetabolites (An antimetabolite is a chemical that inhibits the use of a metabolite, which is another chemical that is part of normal metabolism)

Question Answer
What are the 3 antimetabolite drugs mentioned?Methotrexate
Cytosine arabinose
Methotrexate is an antimetabolite/acts as an antagonist for what?Folate antagonist
Folate antagonist?Methotrexate
What are folates necessary for?Essential in synthesis of Purine nucleotides & Thymidylate, which are necessary for DNA synthesis & cell division
What is the effect of Methotrexate on cancerous cells (once you know that it is an antimetabolite for & what the thing it's antagonizing does)Inhibit DNA synth & cell division
HOW does Methotrexate get into the cells? (What is the solubility of Methotrexate? How does this affect it's ability to get into the cell?)Methotrexate has a LOW lipid solubility, however, that doesn't really affect it much bc it is taken up into the cell via the Folate transport system
The metabolites of Methotrexate stay in the cell for how long?Weeks! (you'll feel like crap after taking meth for weeks)
What are the side effects of Methotrexate?Bone marrow depression & GIT irritation (& it's metabolites stick around for weeks!)
Major side effect/contraindication of 5-fluorouracil?FATAL NEUTROTOXICITY IN CATS!!
Which drug czs a fatal neurotoxicity in cats?5-fluorouracil (5 kills cats. Bc he is neurotically hungry)
How does 5-fluorouracil work?Interference w/ DNA synthesis: Inhibition of thymidylate synthase, blocks DTMP (he had 'synthesis' but I'm pretty sure that's wrong. Either way, inhibits making nuc acids to make DNA) (just like how Flucytosine also messes w/DNA) (5's thighs)
Cytosine arabinose has what properties?Short elimination half-life & crosses BBB (ARABic horses live for a short time bc they have no BBB)