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
2
Q
Which three drugs affect purine synthesis?
A
- Mercaptopurine
- Thioguanine
- Methotrexate
3
Q
What two drugs affect the synthesis of DNA from deoxy nucleotides?
A
- Fluorouracil
- Cytarabine
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
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
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
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
8
Q
What class of antimetabolite is Gemcitabine? What cancers is it used to treat?
A
- Pyrimidine analog
- Pancreatic, ovarian, lung
9
Q
What class of antimetabolite are 6-Mercaptopurine and Thioguanine? What cancers are they used to treat?
A
- Purine analogs
- ALL, AML
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
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
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
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
14
Q
What are the MOR to MTX?
A
- Decreased uptake
- Increased efflux
- Attenuation of polyglutamation processes
- Changes in DHFR structure and expression
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
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
