Anti-Cancer Drugs: Antimetabolites Flashcards Preview

Block 2 Pharmacology > Anti-Cancer Drugs: Antimetabolites > Flashcards

Flashcards in Anti-Cancer Drugs: Antimetabolites Deck (33):
1

What are antimetabolites?

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

2

Which three drugs affect purine synthesis?

1. Mercaptopurine

2. Thioguanine 

3. Methotrexate

3

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

1. Fluorouracil 

2. Cytarabine

4

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

5

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 

6

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  

7

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

- Aka, cytosine arabinoside 

- Pyrimidine analog 

- AML, ALL, Non-Hodgkin lymphoma

8

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

- Pyrimidine analog 

- Pancreatic, ovarian, lung 

9

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

- Purine analogs 

- ALL, AML

10

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  

11

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 

12

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

13

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

14

What are the MOR to MTX?

- Decreased uptake 

- Increased efflux 

- Attenuation of polyglutamation processes

- Changes in DHFR structure and expression

15

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

16

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 

17

What are the MOR to 5-FU?

- Decreased activation of 5-FU 

- Mutation or upregulation of TS 

- Feedback: unbound enzyme inhibits own mRNA (?)

 

 

18

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

19

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

20

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

21

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)

22

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

23

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)

24

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

25

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

26

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)

27

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

28

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

29

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 


 

30

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 

31

What is Thioguanine?

- 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

What is Hydroxyurea?

- 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

What about teratogenicity though, yo?

- 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