What are antimetabolites?
Drugs that interrupt the assembly of new DNA that is essential to cell division
Which three drugs affect purine synthesis?
What two drugs affect the synthesis of DNA from deoxy nucleotides?
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
What is the MOA of 5-FU?
- Converted in cells to FdUMP (5-fluoro-2-deoxyuridine-5-monoP): DNA syn inhibition by inhibiting thymidylate synthase (TS) -> "thymineless death"
- Additional intermediary conversion produces further fluorinated products which inhibit other enzymes:
1. FdUTP (5-fluorodeoxyuridine-5-triphosphate): incorporated into DNA, inhibiting syn and function
2. FUTP (5-fluoroidine-5-triphosphate): interferes with mRNA translation
What are the MOR to 5-FU?
- Decreased activation of 5-FU
- Mutation or upregulation of TS
- Feedback: unbound enzyme inhibits own mRNA (?)
Describe 5-FU toxicity.
- Administered IV
- Acute chest pain; ischemia
- Myelosuppression: anemia, mucositis, diarrhea (less via drug infusion)
- Hand-foot syndrome: redness, swelling, tingling, thick calluses/blisters on palms/soles, tenderness
1. More common w/longer duration drug infusion, and also seen with Capecitabine & Cytarabine
What is hand-foot syndrome? Which antimetabolites cause it?
- Redness (like sunburn), swelling, tingling or burning sensation, skin tightness, tenderness, thick calluses or blisters on palms and soles (sometimes knees and elbows)
- Caused by escape of anticancer drug from capillaries in these areas of the body, with subsequent tissue damage locally (may cause difficulty walking)
- 5-FU, Capecitabine, Cytarabine
Why would you use Leucovorin with 5-FU? What other drug is it used with?
- Increases formation of TS complex, enhancing response to 5-FU -> adjunctive therapy to drive intermediary metabolism into incorporating fluorouracil, enhancing its activity against TS and associated enzymes
- Used with 5-FU in treatment of colon cancer (IV, sequentially)
- Also used with MTX
Tell me everything about Capecitabine. Everything. Then tell me more.
- Essentially a pro-drug for 5-FU, metabolically converted to active form IC (via carboxylesterase, cytidine deaminase, and thymidine phosphorylase; latter two found in many tissues and tumors)
- Oral agent (unlike 5-FU); treats metastastic breast and colorectal
- Toxicities similar to those for 5-FU (myelosuppression and diarrhea), but hand and foot syndrome more common (and may require dose reduction or cessation of therapy)
What is the MOA of Cytarabine?
- Pyrimidine antimetabolite requiring IC activation
- Converted to ARA-CTP, and 2-hydroxyl hinders 3-D bond rotation, interfering with base stacking -> tumors unable to remove ARA-CTP, inhibiting chain elongation, and leading to shortened DNA strands
- Multiple DNA strand duplication increases possibility for recombination
- Most specific antimetabolites for cell cycle S phase; IV, SC, ITH because poor bioavailability
What are the MOR to Cytarabine?
- Decreased cellular uptake
- Decreased metabolic activation: less ARA-C -> ARA-CTP
- Increased inactivation by cytidine deaminase to inactive metabolite, uracil arabinoside (ARA-UMP)
What are the adverse effects of Cytarabine?
- Potent myelosuppressive agent: severe leukopenia, thrombocytopenia, and anemia; megaloblastic changes
- GI, stomatitis (canker sores, cold sores, and other irritations in the mouth)
- Reversible hepatic enzyme elevations
- Non-cardiogenic pulmonary edema, which seems to be linked to experimental high-dose therapy
How does Cytarabine improve results in remission induction and consolidation?
- High-dose regimens used to saturate enzymes
- Remission induction: first in series of therapeutic measures taken to control cancer
- Consolidation: treatment given after induction therapy to consolidatethe gains obtained, further reduce the number of cancer cells, and enhance the likelihood of a durable, complete remission
Gemcitabine. Go. Alliteration.
- MOA: deoxycitidine analog converted to active di-P and tri-P nucleotide forms IC -> incorporation into DNA results in chain termination
- Kinetic differences (vs. Cytarabine): 1 more bp added, repair > difficult, > penetration/retention, > kinase affinity
- Infusion: saturate enzymes
- Toxicity: myleosuppression, flu-like syndrome, asthenia (weakness), increased liver transaminases (ALT, AST), interstitial pneumonitis (steroid responsive)
What is the MOA of 6-MP? What are its two alternative pathways? Why should you care?
- Activated by hypoxanthing-guanine-phosphoribosyl-transferases (HGPRTases) to toxic nucleotides that inhibit several enzymes involved in purine metabolism
- Can be converted to 2 o/products: 6-thiouric acid (inhibited by allopurinol) and 6-methyl-mercaptopurine (via TPMT) -> impacts drug toxicity
1. Allopurinol: increased mercaptopurine toxicity, and drug dose should be reduced accordingly
2. Thiopurine methyltransferase (TPMT): significant interpatient variability in its capacity
Describe the mechanisms of TPMT variability. How is the discovery of these useful therapeutically?
- Single nucleotide polymorphisms (SNPs) in enzyme
- Genetic polymorphisms may lead to 3 clinical TPMT activity phenotypes: high, intermediate, and low activity,
1. Associated with differing rates of inactivation of thiopurine drugs (meracaptopurine, thioguanine, and azathioprine) and altered toxicity risks
- Over 90% of phenotypic TPMT variability across pops be accounted for with 3 point mutations defined by 4 non-functional alleles: 2, 3A, 3B, and 3C
1. Genotyping pediatric pts for polymorphism and adjusting drug doses = maintained anticancer activity, and significantly less extreme toxicity
What are the MOR to Mercaptopurine?
- Decreased or complete lack of HGPRT
- Decreased drug uptake, increased efflux
- Altered enzyme structure
- Altered recognition of DNA breaks
Describe the toxicity of Mercaptopurine.
- Pharmacogenomics: erythrocyte TPMT test
- Slow onset bone marrow suppression
- Jaundice and increased hepatic enzymes
- REDUCE dose with Allopurinol (to 25%) -> avoid excessive toxicity