Cancer treatment - Traditional Chemotherapy - Antimetabolites (1) Flashcards
Are antimetabolite chemotherapeutics cell cycle specific or non specific?
They are cell cycle specific - s phase specific
Which drugs are antimetabolites for cancer treatment?
- Methotrexate
- Pemetrexed
- Fludarabine
- Cytarabine
- Gemcitabine
- 5-Fluorouracil
- Capecitabine
- 6-mercaptopurine
How do antimetabolites work? (in general)
They inhibit DNA synthesis
(therefore they are s phase specific - this is the phase during which DNA replication occurs)
What is the difference in using antimetabolites for autoimmmune disease vs cancer?
They are used at much lower doses for auto-immune diseases
Methotrexate MOA (2)
MTX is a folic acid analog - looks like folic acid with 2 slight differences
Dehydrofolate reductase (DHFR)
MTX binds to and inhibits DHFR, inhibiting the formation of THF (thus inhibiting DNA synthesis)
Polyglutamate derivatives of MTX also have cytotoxic action
How does the structure of MTX effect resistance?
MTX is highly water soluble - it needs carrier receptors to get inside of cells
Cancer cells downregulate these carrier receptors (RFC, folate receptor) and increase p-gp (which increases efflux from cell) - thus establishing resistance
Since MTX is not ____________ it can not be used to treat _________________
MTX is not lipophilic, so it can not be used to treat brain tumors (doesn’t cross BBB)
MTX route of administration for chemo?
IV
(not used PO or subq for chemo)
What is the dose limiting toxicity of methotrexate? What should be done because of this?
Myelosuppression
Because of severe myelosuppression - leucovorin rescue therapy should be given with high dose methotrexate chemo - should be given 24 hours after the end of the MTX infusion
MTX acute ADRs (5)
Dose limiting - myelosuppression
Nephrotoxicity
Hepatoxicity
Mucositis
Neurotoxicity
MTX chronic ADRs (2)
Hepatic fibrosis
Pneumonitis
MTX DDIs (7)
There are a lot of drug interactions with MTX, the following drugs should be held for at least 48 hours before starting the MTX infusion and for 5 days following infusion - otherwise they interfere with MTX clearance and can cause nephrotoxicity ….
- Penicillin
- Sulfonamides
- Tetracyclines
- Ciprofloxacin
- NSAIDs
- Salicylates
- PPIs
Prevention of toxicity with high dose MTX (5)
- Check renal function before starting
-renal dose adjustments required - Discontinue interacting mediations
-for 48 hours before administration of MTX and for 5 days after (interacting medications delay clearance and can cause nephrotoxicity) - Urine alkalization and IV hydration
-helps clear MTX better (to avoid nephrotoxicity)
-give sodium bicarb infusion until urine pH is at least 7 (sometimes patients take sodium bicarb tablets at home beforehand to save time) - Monitor MTX levels periodically
-12 and 24 hours after infusion - Leucovorin rescue therapy
-should be started 24 hours after the end of the infusion (this is a folate analog - helps with myelosuppression)
What can be used if MTX toxicity occurs?
Glucarpidase
-If MTX level is > 1 micromole/L with delayed clearance and renal impairment
Pemetrexed MOA
Inhibits thymidylate synthetase
-which inhibits dihydrofolate synthesis, and therefore DNA synthesis
Pemetrexed pre-treatment (3)
- Folic acid
-(instead of leucovorin rescue therapy like with MTX)
-folic acid PO starting 7 days prior to infusion and for 21 days after
-to help with myelosuppression - Vitamin B12
-given IM once, 7 days prior to infusion and every 3 cycles thereafter
-to prevent anemia - Dexamethasone
-PO BID x 3 days, starting 1 day before infusion
-to prevent skin pealing (desquamation) and rash
Pemetrexed DDI (1)
NSAIDs
-these delay clearance of pemetrexed
-discontinue for 2-5 days before infusion and for 2 days after
(but doesn’t interact with all those other agents like MTX)
What is the dose limiting ADR of pemetrexed?
Myelosuppression
-particularly thrombocytopenia
Pemetrexed ADRs (4)
Myelosuppresion (dose limiting)
Skin peeling/rash (desquamation)
Mucositis
Diarrhea (not too severe)
Fludarabine MOA
Purine analog (antagonist)
Inhibits DNA polymerase
Causing DNA strand breaks and apoptosis (inhibits DNA replication = antimetabolite)
What is the dose limiting toxicity of fludarabine?
Myelosuppression
Fludarabine nadir considerations
Thrombocytopenia nadir is slightly more prolonged than neutropenia nadir…
Neutropenia nadir = ~13 days
Thrombocytopenia nadir = ~16 days
Fludarabine ADRs/considerations (3)
Myelosuppression - dose limiting
Neurotoxicity (delayed symptoms- 3-4 weeks after infusion)
Increased risk of infections
-prophylax for PCP (with Bactrim)
Cytarabine and gemcitabine MOA
Pyrimidine antagonists
Modified sugar moieties, integrate into DNA - inhibit DNA polymerase, and therefore DNA synthesis (= antimetabolites)
Gemcitabine is one of the most important drugs for treating what type of cancer?
Pancreatic cancer
Cytarabine standard vs high dose toxicities
Standard
-dose limiting toxicity is myelosuppression
-rash
High dose
-dose limiting toxicity is cerebellar syndrome (ataxia, difficulty walking and speaking)
-conjunctivitis (dexamethasone eye drops should be given during and after infusion)
-hand foot syndrome (numbing/tingling/swelling)
Gemcitabine ADRs
Dose limiting toxicity - myelosuppression (specifically thrombocytopenia)
Others:
-skin rash
-peripheral edema
-hepatotoxicity
-flu like symptoms
-drug fever
5-Fluorouracil MOA (2) - and how this relates to administration of the drug
Prodrug, similar in structure to uracil but with a fluoride
It is metabolized to a nucleotide which is the active drug - cells will think that this is a pyrimidine, binds to an inhibits thymidylate synthetase - resulting in no thymine production - inhibiting DNA synthesis - resulting in cell death
Also… uracil is part of RNA- so it will also incorporate into RNA and inhibit RNA synthesis and protein translation
The DNA synthesis inhibition occurs with continuous administration of the drug (over time)
The RNA inhibition occurs right away
So we give a bolus dose, followed by a continuous infusion
What drug is given to enhance the function of 5-FU, how does this work?
Leucovorin is given with 5-FU
-5-FU binds to thymidylate synthetase (inhibiting formation of thymine) - leucovorin enhances the affinity between 5-FU metabolites and the thymidylate synthetase - thus enhancing the anticancer effect
5-FU is often used in combination with ___________ for treatment of _____________
Oxaliplatin for treatment of colorectal cancer
5-FU Metabolism consideration
5-FU is metabolized by DPD (Dihydropyrimidine dehydrogenase) into an inactive metabolite
-some people may have DPD deficiencies - so they will have increased toxicities (hematologic and diarrhea)
-so we test people for enzyme expression before giving
5-FU DDI
Warfarin
-causes increased INR - so dose of warfarin should be decreased (or switch to another agent)
What is the dose limiting toxicity of 5-FU bolus vs continuous infusion
bolus = myelosuppression
continuous infusion = GI toxicity (diarrhea - very severe)
5-FU ADRs
General ADRs -
photosensitivity (counsel patients to use sunscreen, avoid exposure)
rash
hand foot syndrome
Bolus dose limiting ADR - myelosuppression
Continuous infusion dose limiting ADR - diarrhea
Other continuous infusion adrs:
-mucositis
-coronary vasospasm
5-FU administration
IV only (due to short half life)
Capecitabine MOA/administration considerations
Oral prodrug for 5-FU
Error prone dosing- taken BID for 2 weeks, and then not taken for 1 week
Capecitabine DDI
Warfarin (increases INR, decrease warfarin dose or change drug)
Capecitabine dose limiting toxicity
Myelosuppression
Capecitabine ADRs
Dose limiting - myelosuppression
❖Hand-foot syndrome
❖Mucositis
❖Diarrhea
❖Bilirubin elevation
❖Cardiotoxicity
Capecitabine contraindication
CrCl < 30 mL/min
Mercaptopurine (6-MP) and Thioguanine (6-TG) MOA
Similar to purines - function as fake purines, get into the cell, inhibit DNA synthesis as a result
What should patients be screened for before taking mercaptopurine?
TPMT enzyme
-TPMT metabolized 6-MP into an inactive metabolite, if patient has deficiency in TPMT, it will go down the other pathway more - resulting in more active toxic metabolite … which can result in more bone marrow suppression
-dose reduction may be needed if they have less TPMT expression
