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block 2 pharmacology > Anti-Cancer Drugs: Antimetabolites > Flashcards

Anti-Cancer Drugs: Antimetabolites Flashcards

1
Q

What are antimetabolites?

A

Drugs that interrupt the assembly of new DNA that is essential to cell division

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2
Q

Which three drugs affect purine synthesis?

A
  1. Mercaptopurine
  2. Thioguanine
  3. Methotrexate
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3
Q

What two drugs affect the synthesis of DNA from deoxy nucleotides?

A
  1. Fluorouracil
  2. Cytarabine
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4
Q

What is azacitidine?

A
  • 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
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5
Q

What class of antimetabolite is Methotrexate? What cancers is it used to treat?

A
  • Folic acid analog
  • ALL, breast, head and neck, lung, osteogenic sarcoma, bladder
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6
Q

What class of antimetabolite are Fluorouracil and Capecitabine? What cancers are they used to treat?

A
  • Pyrimidine analogs
  • Breast, colon, esophageal, stomach, pancreas head and neck
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7
Q

What class of antimetabolite is Cytarabine? What cancers is it used to treat?

A
  • Aka, cytosine arabinoside
  • Pyrimidine analog
  • AML, ALL, Non-Hodgkin lymphoma
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8
Q

What class of antimetabolite is Gemcitabine? What cancers is it used to treat?

A
  • Pyrimidine analog
  • Pancreatic, ovarian, lung
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9
Q

What class of antimetabolite are 6-Mercaptopurine and Thioguanine? What cancers are they used to treat?

A
  • Purine analogs
  • ALL, AML
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10
Q

What is the MOA of Methotrexate?

A
  • 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
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11
Q

What is the role of polyglutamation in the cellular activity of Methotrexate (MTX)?

A
  • 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
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12
Q

What is Leucovorin rescue?

A
  • 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
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13
Q

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.

A
  • 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
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14
Q

What are the MOR to MTX?

A
  • Decreased uptake
  • Increased efflux
  • Attenuation of polyglutamation processes
  • Changes in DHFR structure and expression
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15
Q

Describe MTX toxicity.

A
  • 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
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16
Q

What is the MOA of 5-FU?

A
  • 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
17
Q

What are the MOR to 5-FU?

A
  • Decreased activation of 5-FU
  • Mutation or upregulation of TS
  • Feedback: unbound enzyme inhibits own mRNA (?)
18
Q

Describe 5-FU toxicity.

A
  • 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
19
Q

What is hand-foot syndrome? Which antimetabolites cause it?

A
  • 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
20
Q

Why would you use Leucovorin with 5-FU? What other drug is it used with?

A
  • 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
21
Q

Tell me everything about Capecitabine. Everything. Then tell me more.

A
  • 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)
22
Q

What is the MOA of Cytarabine?

A
  • 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
23
Q

What are the MOR to Cytarabine?

A
  • Decreased cellular uptake
  • Decreased metabolic activation: less ARA-C -> ARA-CTP
  • Increased inactivation by cytidine deaminase to inactive metabolite, uracil arabinoside (ARA-UMP)
24
Q

What are the adverse effects of Cytarabine?

A
  • 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
25
Q

How does Cytarabine improve results in remission induction and consolidation?

A
  • 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
26
Q

Gemcitabine. Go. Alliteration.

A
  • 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)
27
Q

What is the MOA of 6-MP? What are its two alternative pathways? Why should you care?

A
  • 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
28
Q

Describe the mechanisms of TPMT variability. How is the discovery of these useful therapeutically?

A
  • 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
29
Q

What are the MOR to Mercaptopurine?

A
  • Decreased or complete lack of HGPRT
  • Decreased drug uptake, increased efflux
  • Altered enzyme structure
  • Altered recognition of DNA breaks
30
Q

Describe the toxicity of Mercaptopurine.

A
  • Pharmacogenomics: erythrocyte TPMT test
  • Slow onset bone marrow suppression
  • Jaundice and increased hepatic enzymes
  • REDUCE dose with Allopurinol (to 25%) -> avoid excessive toxicity
31
Q

What is Thioguanine?

A
  • Similar MOA: RNA/DNA syn inhibition, incorporation of thionucleotides in RNA/DNA (oral, like 6-MP)
  • Similar resistance mechanisms (i.e., decreased uptake, increased efflux, HGPRT modification or downregulation, etc.)
  • No conflict with Allopurinol (no 6-thiouric acid pathway)
  • Bone marrow suppression dose-limiting (like 6-MP), but hepatic dysfunction via cholestasis & jaundice also observed
32
Q

What is Hydroxyurea?

A
  • Non-antimetabolite that prevents DNA formation
  • Oral free radical scavenger (at catalytic center of ribonucleotide reductase subunit) captures transient free radical necessary for conversion of ribonucleotides to deoxyribonucleotides, preventing final synthetic step (rate-limiting), and inhibiting cell division
  • Resistance by reductase upregulation
  • Toxicities: hematopoietic depression, desquamative interstitial pneumonitis, GI disturbances, maculopapular rash, dermatomyositis-like skin changes, peripheral and facial erythema, skin cancer, ulceration, and darkening
33
Q

What about teratogenicity though, yo?

A
  • Most anticancer drugs exhibit both teratogenicity and an ability to make the male or female patients infertile (due to effects on essential cellular processes)
  • Under some circumstances, harvesting and freezing of sperm and/or eggs can be used to overcome this problem if surviving patient later considers having a child
  • GUNNER LIST: busulfan, cisplatin, cyclophosphamide, ifosfamide, melphalan, cytarabine, 5-FU, methotrexate, vincristine, vinblastine, bleomycin, doxorubicin, daunorubicin

block 2 pharmacology (8 decks)

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