Anti-Cancer Drugs: Antimetabolites Flashcards
What are antimetabolites?
Drugs that interrupt the assembly of new DNA that is essential to cell division
Which three drugs affect purine synthesis?
- Mercaptopurine
- Thioguanine
- Methotrexate
What two drugs affect the synthesis of DNA from deoxy nucleotides?
- Fluorouracil
- Cytarabine
What is azacitidine?
- Not covered in this lecture, but Dr. Sweatman did provide a brief description… So, here it is:
- Injectable cytosine analog incorporated into RNA and DNA, inhibiting protein synthesis & promoting apoptosis
- Used primarily in the tx of myelodysplastic syndrome, a condition in which red cells, white cells & platelets don’t mature successfully and crowd out healthy cells, so pt. is susceptible to anemia, infection and bleeding problems
What class of antimetabolite is Methotrexate? What cancers is it used to treat?
- Folic acid analog
- ALL, breast, head and neck, lung, osteogenic sarcoma, bladder
What class of antimetabolite are Fluorouracil and Capecitabine? What cancers are they used to treat?
- Pyrimidine analogs
- Breast, colon, esophageal, stomach, pancreas head and neck
What class of antimetabolite is Cytarabine? What cancers is it used to treat?
- Aka, cytosine arabinoside
- Pyrimidine analog
- AML, ALL, Non-Hodgkin lymphoma
What class of antimetabolite is Gemcitabine? What cancers is it used to treat?
- Pyrimidine analog
- Pancreatic, ovarian, lung
What class of antimetabolite are 6-Mercaptopurine and Thioguanine? What cancers are they used to treat?
- Purine analogs
- ALL, AML
What is the MOA of Methotrexate?
- Primarily a dihydrofolate reductase inhibitor, but also inhibits thymidilate synthase and two early enzymes in purine biosyn pathway: glycinamide ribonucleotide transformase (GARFT) and aminoimidazole carboxide ribonucleotide transformylase (AICARFT)
- Folic acid essential dietary factor b/c tetrahydrofolate cofactors provide C groups for DNA (thymidilate and purines) and RNA (purine) synthesis -> inhibits cellular replication
- Also leads to accumulation of adenosine, thought to be responsible for anti-inflammatory drug effects
What is the role of polyglutamation in the cellular activity of Methotrexate (MTX)?
- MTX taken into cell via folate uptake process, and can be effluxed by ABC transporters
- Within cell, however, MTX polyglutamated and “trapped” inside cell -> both PG-MTX and PG-dihydrofolic acid retain ability to inhibit their enzyme targets
What is Leucovorin rescue?
- Early admin of Leucovorin (oral or IV) to prevent fatal bone marrow toxicity possible w/high MTX doses
- Leucovorin is folinic acid (5-formyltetrahydrofolate), and has activity equivalent to folic acid, and is thus readily converted to tetrahydrofolate, but DOES NOT require DHFR for its conversion -> allows for some purine and pyrimidine biosyn
1. Rescues normal cells from effects of folate antagonists, and modulates effects of 5-FU -> used to treat megaloblastic anemias
We have now learned about 3 drugs that interfere with the availability of tetrahydrofolate. Why are some toxic to humans, and others not? Be specific.
- Pyrimethamine (anti-mallarial) and Trimethoprim (AB) have specificity for their respective targets (by several orders of magnitude), and do NOT produce significant host toxicity
- Methotrexate IC50 about the same for E. Coli (0.1), malaria (0.7), and man (0.2), so it produces host toxicity
What are the MOR to MTX?
- Decreased uptake
- Increased efflux
- Attenuation of polyglutamation processes
- Changes in DHFR structure and expression
Describe MTX toxicity.
-
Myelosuppression: lymphoproliferative disorders, bone marrow, anemia (spontaneous hemorrhage or life-threatening infection)
1. Anemia in RA or psoriasis (MTX and 5-FU) - GI toxicity (diarrhea), N/V, abdominal distress
- Pneumonitis: patchy inflammatory infiltrates, fibrosis
-
Weak acid: precipitates in tubules, but can hydrate and alkalinize urine to promote excretion
1. Majority eliminated via urine (GF and RTS), esp. in first 12 hrs after admin -> any drugs interfering with renal excretion (i.e., NSAIDs or probenacid inhibitor of RTS) can reduce MTX clearance and potentially increase drug associated toxicity