Antimetobolites Flashcards
What antimetabolites work as folic acid analogs?
Methotrexate
What antimetabolites work as pyrimidine analogs?
- Flurouracil (5-FU)
- Capecitabine
- Cytarabine (cytosine arabinoside)
- Gemcitabine
What antimetabolites work as Purine Analogs?
• 6-Mercaptopurine (6-MP)
- Thioguanine
- Fludarabine
Methotrexate
- Intake, Retention?
- MOA
Taken in via ABC transporters and POLYGUTAMATED causing it to get trapped inside the cell (*this version is still effective)
- Dihyrdofolate Reductase Inhibitor (DHFR)Pyrimidine
Synthesis Block:
- Thymidylate Synthase Inhibition (TS) Purine
Synthesis Block:
- Glycinamide Ribonucleotide Transformylase (GARFT) and ribonucleotide transformylase (AICARFT)
At Higher than usual doses what is the major adverse effect of methotrexate?
- how do we combat this effect?
- explain this processes
Bone Marrow Toxicity is High doses
Combat Effect by:
- LEUCOVORIN RESCUE
Leucovorin:
aka Folinic Acid - does not need DHFR for conversion so purine and pyrimidine synthesis can resume
Why don’t other drugs that inhibit DHFR like Trimetoprim and Pyrimethamine get used for cancer?
They are target specifically for non-human DHFRs making them inaffective against cancer
How is Methotrexate Resistance conferred?
- What are some other toxic effects of MTX besides bone marrow toxicity?
- Elimination?
- Drug -Drug interactions?
Resistance:
- Less uptake by ABC trasporters
- Less Polyglutamation
- More DHFR production
Toxicity:
- Pulmonary Infiltrates and Fibrosis
Elimination:
- Renal via GF and Tubules NSAIDs may inhibit Tubular secretion leading to Increased MTX toxicity
5-Fluorouracil; 5-FU [adrucil]
Method of Administration
MOAs
Delivered IV only
DNA synthesis Inhibition
- Inhibits Thymidine Synthase
Incorporation into DNA:
- Inhibits DNA synthesis
Translation inhibitor:
- Interferes with mRNA translation
What 3 antimetabolites cause hand and foot syndrome?
- 5-Fluorouracil (IV)
- Capecitabine (PO)
- Cytarabine
5-Flurouracil
- Resistance mechanisms
- Toxicity
Resistance:
- Thymidine Synthase Upregulation or Mutations
- Decreased Activation of 5-FU
Toxicity:
- Acute Chest pain
- Other usual (myelosupp., GI, anemia, etc.)
- HAND-FOOT SYNDROME
***Note: Hand and foot more common with acute drug infusions
What is hand and foot syndrome?
- cause?
Symptoms:
- Redness of Hands and Feet
- Tingling Sensations
- Swelling
- Blisters
Cause:
- Drug escapes from capillaries and irritates the skin in these areas of the body
Why would you use Levocovorin with 5-FU?
- Drives intermediary Metabolism into Incorporating 5-FU (IV) into Thymidine Synthase
**Remember Levocovorin is also used in Bone Marrow Rescue with Methotrexate
What is the oral version of 5-FU?
- differences in side effects?
Capecitabine [xeloda]
**essentially just a 5-FU pro-drug- Hand and Foot Syndrome occurs more frequently with this drug
What is the most specific of the Anti-metabolites for the S-phase of the cycle?
Cytarabine; ARA-c [cytosar]
Cytarabine; ARA-C [cytosar]
MOA
administration method?
MOA:
- ARA-CTP (triphosphate)
- Gets incorporated into growing chain and creates STERIC hinderance with 2’-hydroxyl
Administered: - IV- SC- ITH (intrahecally)
How is resistance to Cytarabine ARA-C conferred?
- Toxicity?
- Decreased Cellular Uptake
- Decreased Phosphorylation to make ARA-CTP
- Increased ARA-C —> ARA-UMP (inactive)
Toxicity:
- Usual (Myelosupp., G.I. effects, thrombocytopenia)
- STOMATITIS
- Hepatic Enzyme Elevations
Gemcitabine [gemzar]
MOA
Toxicity
MOA:
- Must be TriPhosphorylated (like ARA-C)
- 1 additional base pair added making repair more difficult
- Better Penetration/Retention
Toxicity:
- Same as all others
- Pneumonitis
Mercaptopurine [purinethol]
MOA
- Administration method?
- Reasons to Dose adjust?
MOA: - 6 Mecraptopurine (6-MP) gets converted to 6-thioinosine monophosphate by HGPRT
- Ultimately becomes 6-Thioguanine Monophosphate and inhibits DNA synthesis
Administration: Oral
***Dose adustment:
1) ALLOPURINOL - blocks 6-thiouric acid (side pdt) formation leading to Toxicity of 6-MP (reduce to 25% of original 6-MP dose)
2) TPMT - converts 6-MP to 6-methyl-MP, Activity of this enzyme is determined by SINGLE NUCLEOTIDE polymorphisms (3 levels of activity)
Mechanisms of Resistance to Mercaptopurine (PO)?
- Toxicity?
Resistance:
- Lowered of HGPRT
- Less drug uptake, more efflux
- Recognition of DNA breaks
Toxicity:
- Bone marrow depression (like always)
- Jaundice and Hepatic Enzymes may Increase
How do you know how much Mercaptopurine to give someone?
***Do Genetic tests to see which version of TMPT they have (polymorphic gene with 3 different possible levels of activity) (remember HGPRT is involved in Lesch-Nyhan syndrome)
Thioguanine; 6-TG [tabloid] - MOA
- resistance
- Toxicity
MOA:
- Same as 6-MP EXCEPT NO 6-thiouric acid conversion so NO conflicts with Allopurinol
Resistance (same as 6-MP)
- Lowered of HGPRT
- Less drug uptake, more efflux
- Recognition of DNA breaks
Toxicity:
- Bone Marrow Suppression
- Hepatic/Jaundice
Hydroxyurea [hydrea]
- MOA
- resitance?
- Toxicity
MOA:
- Free Radical Scavenger that grabs a free radical needed in the conversion of ribonucleotides to DEOXYribonucleotides (RATE LIMITING step)
Resistance:
- Upregulation of Ribonucleotide Reductase
Toxicity:
- Bone Marrow Depressino- RASHES, ERYTHEMA, ULCERATIONS, SKIN CANCER, SKIN DARKENING
What is the difference between Hydroxyurea and Antimetabolites?
Hydroxyurea doesn’t pretend to be a nucleotide or nucleotide intermediate it just inhibits the RATE LIMITING step in nucleotide synthesis
Which of the Antimetabolite drugs have resistance conferred against them by decreasing their activation?
- Mercptopurine and Thioguanine (HGPRT and pathway)
- Gemicitabine and Cytarabine ARA-C (triphos. activation)
- 5-FU
Which of the antimetabolites are resisted by inactivation?
Most Purine and Pyrimidine Antimetabolites
How is accumulation of drug within the cell prevented with the antimetabolites, MTX?
P-gp- can efflux just about any drug out
MTX- polyglutamation is needed to keep it in the cell, if this doesn’t happen MTX is no longer effective
What reproductive effects do most anti-cancer drugs have?
- Most drugs are TERATOGENS
- Most also cause INFERTILITY
What are some cancer drugs that may cause Red urine.
Explain the difference in each.
Cyclophosphamide: - causes hemorrhagic cystitis leading to RBCs in the urine
Doxyrubicin:
- causes red urine because its metabolites are red (not because its causing disease)
T or F: the Platinum drugs are considered alkylating agents.
False, they are platininating agents, not alkylating agents
T or F: in some cases cancer cells can just upregulate DNA excision repair mechanisms to remove antimetabolites and keep moving on.
True.
