Cancer III - Antimetabolites Flashcards Preview

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Flashcards in Cancer III - Antimetabolites Deck (49):
1

Antimetabolite Drugs:

1. Folic acid analogs?

2. Purine analogs?

 

Antimetabolite Drugs:

1. Folic acid analogs = methotrexate

2. Purine analogs = 6-mercaptopurine, 6-thioguanine, and fludarabine

2

Antimetabolite Drugs:

1. Pyrimidine analogs?

2. One other drug?

Antimetabolite Drugs:

1. Pyrimidine analogs = 5-fluorouracil, cytosine arabinoside (Ara-C), and gemcitabine

2. Hydroxyurea

3

Antimetabolites:

1. Structural similarity to _____ intermediates. Act as?

2. Interfere with production of?

3. Some inhibit production of _____ and thus inhibit?

4. Others have similar structures to _____ ____ which can?

Antimetabolites:

1. Similar to physiological intermediates and act as substrates in biochemical reactions

2. Interfere with production of nucleic acids

3. Some inhibit pdtn of dNTPs and thus inhibit DNA replication

4. Others hve similar structures to normal nucleosides which can compete for anabolic enzymes and incorporate into RNA and DNA --> cytotoxic effect

4

Purines and Pyrimadines:

1. Which is a single ring? Double?

2. Which bases are purines?

3. Which are pyrimidines?

Purines and Pyrimadines:

1. Single ring = pyrimidine; double = purine

2. Purines = Adenine and guanine

3. Pyrimidines = cytosine, thymine, and uracil

5

Inhibition of purine nucleotide synthesis:

1. Which drugs?

2. What do they inhibit?

Inhibition of purine nucleotide synthesis:

1. 6-mercaptopurine and 6-thioguanine

2. Inhibit phosphoribosyl pyrophosphate (PRPP) aminotransferase

6

Inhibition of purine nucleotide synthesis:

1. Functions of 6-mercaptopurine (6MP)?

2. Functions of 6-thioguanine (6TG)?

3. Resistance of one and response of the other?

Inhibition of purine nucleotide synthesis:

1. 6MP = inhibit PRPP amidotransferase, inhibit conversion of IMP to GMP and AMP, inhibit IMP dehydrogenase (for IMP to GMP)

2. 6TG = inhibit PRPP amidotransferase and inhibits IMP dehydrogenase most selectively than 6MP

3. Resistant to 6MP --> will NOT respont to 6TG; however, some resistant to 6TG --> will respond to 6MP

7

Inhibition of purine nucleotide synthesis:

Other purine inhibitors:

1. What is the function of dihydrofolate (DHF) reductase? What drugs inhibit it?

2. What is the function of ribonucleotide reductase (RR)? What is it inhibited by?

Inhibition of purine nucleotide synthesis:

Other inhibitors:

1. DHF reductase: generates purine ring; inhibited by methotrexate and trimetrexate (for tumors resistant to methotrexate)

2. RR = conversion of ADP--> dADP and GDP --> dGDP; inhibited by fludarabine and hydroxyurea

8

Folic Acid analogs:

Name 3 drugs.

Inhibition of purine nucleotide synthesis:

a. methotrexate

b. trimetrexate

c. pemetrexed

9

Methotrexate:

1. Normal function of folic acid?

2. Primary MOA?

Methotrexate:

1. Folic acid is an essential dietary factor required for synthesis of precursosrs of DNA (thymidylate and purines) and RNA (purines)

2. MOA: inhibits DHF reductase which leads to depletion of tetrahydrofolate (THF) cofactors required for synthesis of thymidylate and purines

10

Methotrexate:

1. Requires what?

2. Undergoes conversion to a series of ______ which also inhibits other?

3. Polyglutamation increases _____ of methotrexate for ____ ____ and prevents?

Methotrexate:

1. Requires reduced folate transporter to enter the cell

2. Undergoes conversion to a series of polyglutamates which also inhibit other folate-requiring enzymes for thymidylate and purine synthesis

3. Polyglutamation increases affinity of methotrexate for thymidylate synthetase and prevents egress from the cell

11

Methotrexate:

1. What is used to help treat methotrexate overdose?

2. What drug inhibits thymidylate synthase and AICAR transformylase?

3. What drug inhibits thymidylate synthase and GAR transformylase?

Methotrexate:

1. Leucovorcin (folinic acid) for OD

2. TS and AICAR: FH2(Glun)

3. TH and GAR: 10-CHO-FH2 (Glun)

12

Methotrexate:

1. Of the folic acid analogs which is more lipid soluble? Why is this important?

2. Cytotoxicity of methotrexate is mutifactorial: due to?

3. Methotrexate activates?

Methotrexate:

1. Trimetrexate is more lipid soluble and does NOT require a protein transporter --> useful in transport deficient resistant cells

2. Cytotox is multifactorial due to inhibition of DHFR, decline in THF pools, and increase in DHF concentration

3. Methotrexate activates p53, cell cycle arrest, and apoptosis

13

Methotrexate:

1. What can rescue the cell from the cytotoxicity of methotrexate?

2. What phase is methotrexate active in?

Methotrexate:

1. 5-formyl-THF (leucovorin) can rescue cell from cytotox

2. Active in S phase --> effective in rapidly proliferating tumors

14

Methotrexate:

Absorption/Fate/Excretion:

1. Protein binding relevance?

2. Volume of distribution? Thus, what are contraindications?

3. Used caustion in patients with impaired?

Methotrexate:

Absorption/Fate/Excretion:

1. It is protein bound thus co-administered drugs which displace it from albumin may potentiate toxicity (aspirin, sulfonamides, penecillins)

2. VD = total body water; contra: ascites and pleural effusions

3. Caution with impaired renal function due to excretion

15

Methotrexate:

1. Excreted by the kidney as a ___ of a weak ___. What else is excreted this way?

2. What other drug also interferes with excretion? What is this drug's use? Function of interference?

Methotrexate:

1. Excreted by the kidney as a salt of a weak acidAspirin and penecillins are also excreted this way and they will interfere with urinary excretion of methotrexate

2. Probenecid - for gout - blocks the organinc acid transport system and thus causes interference

16

Methotrexate:

1. Standard dose toxicity?

2. High dose toxicity?

Methotrexate:

1. Standard: myelosuppression, stomatitis, and enteritis

2. High: myelosuppression, stomatitis, enteritis, conjunctivitis, renal failure, neurotoxicity, and very rarely hepatic failure

17

Methotrexate:

Mechanisms of resistance:

1. Impaired ____.

2. Mutation of ____ with decreased ____ for methotrexate

3. Increased levels of DHFR gene ____ or altered gene ____: overexpression of _____ ____

Methotrexate:

Mechanisms of resistance:

1. Impaired transport into cells

2. Mutation of DHFR with decreased affinity

3. Increased levels of DHFR gene amplification or altered gene regulation: overexpression of thymidylate synthase

18

Methotrexate:

Mechanisms of resistance:

1. Decreased synthesis of methotrexate ______

2. Increased expression of drug ____ _____

 

Methotrexate:

Mechanisms of resistance:

1. Decreased synthesis of methotrexate polyglutamates

2. Increased expression of drug efflux transporter

19

Methotrexate:

Uses:

1. Cancer: ____ in kids and what else?

2. Cancer: used in combination therapy for carcinomas of?

3. High dose used for adjuvant therapy in ____ sarcoma.

4. Noncancerous uses?

Methotrexate:

Uses:

1. Cancer: ALL in kids and choriocarcinoma

2. Cancer combo: carcinoma of breast, bladder, ovary, head, and neck

3. Adjuvant in osteogenic sarcoma

4. Noncancerous: psoriasis and RA

20

Purine analogs:

1. 6MP and 6TG are analogs of ___ and ___. Inhibit ___ ___ purine synthesis and become ____ into ____ acids.

2. What normally adds the amine group precursor to the purine base?

3. What inhibits this?

Purine analogs:

1. Analogs of hypoxanthine and guanine. Inhibit de novo purine synthesis and become incorporated into nucleic acids

2. PRPP amidotransferase adds precursor to the base

3. PRPPA is inhibited by 6MP and 6TG

21

Purine analogs:

1. What generates the purine ring?

2. What is this inhibited by?

Purine analogs:

1. Purine ring is generated by DHF reductase

2. Inhibited by methotrexate and trimetrexate

22

Purine analogs:

1. What converts IMP-->GMP and AMP-->IMP?

2. What is this inhibited by?

3. Conversion to GMP is more selectively inhibited by?

Purine analogs:

1. Conversion to GMP/IMP is done by IMP dehydrogenase

2. Inhibited by 6MP and 6TG

3. GMP is more selectively inhibited by 6TG

23

Purine analogs:

1. DNA polymerase is inhibited by ____, or it can be _______ into DNA or RNA.

2. 6MP and 6TG + PRPP are catalyzed by ____. What does this yield?

Purine analogs:

1. DNA pol is inhibited by 6TG, or it can be incorporated

2. Catalyzed by HGPRT; yields 6MP ribose-5'phosphate (T-IMP) and 6TG ribose-5'phosphate

24

Purine analogs:

1. Both T-IMP and 6-thiolGMP can be incorporated into ___, but ___ conversion is less prevalent. More ____ is converted and incorporated into RNA and DNA

2. TIMP is a poor substrate for ___ _____ and it accumulates in cells leading to?

3. TIMP can also inhibit synthesis of?

Purine analogs:

1. Both can be incorporated into DNA, but T-IMP is less prevalent. More 6-thioGMP is converted and incorporated into DNA and RNA

2. TIMP is a poor substrate for guanylyl kinase and it accumulates leading to feed back inhibition which is inhibition of PRPP amidotransferase****

3. TIMP can also inhibit synthesis of AMP and GMP

25

Purine analogs:

Absorption/Fate:

1. 6MP administration?

2. Allopurinol ( a ____ ____ inhibitor) used to decrease hyperuricemia, may cause toxicity and thus the dose must be decreased ____%.

3. Elimination of 6MP and 6TG is ____.

Purine analogs:

Absorption/Fate

1. 6MP: oral or IV

2. Allopurinol ( a xanthine oxidase inhibitor) must have decreased dose by 75% to relieve toxicity

3. Elimination of 6MP and 6TG is hepatic

26

Purine analogs:

1. Toxicity of 6MP and 6TG?

Mechanism of Resistance:

2. Deficiency/lack of ____

3. Decreased drug ____

4. Increased activity of ___ (increased ___)

5. Alteration in inhibition of?

Purine analogs:

1. Toxicity: myelosuppression, GI, and hepatic

Resistance:

2. Lack of HGPRT

3. Decreased drug transport

4. Increased activity of MRP5 (increased efflux)

5. Alteration in inhibition of ribosylamine 5'p synthase

27

Fludarabine:

1. MOA?

2. It is a prodrug _____ intracellularly by _____ kinase.

3. The metabolite inhibits? Ultimate result?

Fludarabine:

1. MOA: purine antimetabolite

2. Prodrug phosphorylated intracellularly by deoxycytidine kinase

3. Metabolite inhibits DNA pol-alpha ribonucleotide reductase, primase, and ligase ultimately inhibiting DNA and RNA synthesis

28

Fludarabine:

1. Causes ____ ____ when incorporated into DNA 

2. Inhibits RNA _____ and ___ _______ when incorporated into RNA

3. Major effect is activation of ____

Fludarabine:

1. Causes chain termination when incorporated into DNA

2. Inhibits RNA processing and mRNA translation 

3. Activation of apoptosis

29

Fludarabine:

1. Route of administration?

2. Patients with compromised ____ function should be treated with caution. Why?

3. Primary use?

Fludarabine:

1. Admin: IV

2. Compromised renal function because renal clearance represents 40% of total body clearance

3. Use: CLL ((B-cell) chronic lymphocytic leukemia)

30

Fludarabine:

1. Toxicity?

2. Resistance is due to decreased activity of ____ ___. How does this normally function?

Fludarabine:

1. Tox: myelosuppression, immunosuppression, N/V, chills, fever, maliase, anorexia, and weakness

2. Decreased activity of deoxycytidine kinase responsible for phosphorylation and conversion of the prodrug

31

Inhibition of pyrimidine nucleotide synthesis:

1. Most frequently targeted step is conversion of ____ to ____ by ____ ___.

2. What two drugs inhibit the above?

Inhibition of pyrimidine nucleotide synthesis:

1. Most frequently targeted step is conversion of dUMP to TMP by thymidylate synthase

2. Inhibited by 5-fluorouracil and FUDR

32

Inhibition of pyrimidine nucleotide synthesis:

1. Reduced production of TTP enhances incorporation of ___ into DNA

2. Conversion of UDP to ____ and CDP to ____ is catalyzed by RR which is inhibited by ______

3. ____ inhibits incorporation of dCTP into DNA by DNA ____

Inhibition of pyrimidine nucleotide synthesis:

1. Enhances incorporation of dUTP into dna

2. Conversion of UDP to dUDP and CDP to dCDP is catalyzed by RR which is inhibited by hydroxyurea

3. Ara-C inhibits incorporation of dCTP into DNA by DNA polymerase

33

Inhibition of pyrimidine nucleotide synthesis:

What are the pyrimidine analogs?

Inhibition of pyrimidine nucleotide synthesis:

a. 5 fluorouracil (5FU)

b. FUDR

c. FTORAFUR

34

Inhibition of pyrimidine nucleotide synthesis:

MOA:

1. Mimics _____ biochemically.

2. What does it require to exert cytotoxic activity?

3. Phosphorylated to what form? What is the product? What is it incorporated into?

Inhibition of pyrimidine nucleotide synthesis:

MOA:

1. Mimics uracil

2. Requires enzymatic conversion

3. Phosphorylated to PPP form and the product FUTP is incorporated into RNA

35

Inhibition of pyrimidine nucleotide synthesis:

MOA:

1. In the presence of ____, FdUMP binds tightly to ____ _____ and traps the enzyme at an intermediate step ( ____ bond is much tighter than ____. ) This prevents ___ of 5FU by ____ ____

2. Coupling of uracil to ___ or ___ allows release of uracil which competes with 5FU for ____ thereby promoting retention of ___

Inhibition of pyrimidine nucleotide synthesis:

MOA:

1. In the presence of THF, FdUMP binds tightly to thymidylate synthase and traps the enzyme at the intermediate step (F-C bond is much tighter than C-H). This prevents methylation of 5FU by thymidylate synthase

2. Coupling of uracil to 5FU or FTORAFUR allows release of uracil which competes with 5FU for DPD thereby promoting retention of 5FU

36

Inhibition of pyrimidine nucleotide synthesis:

1. Metabolized by the ____. Inactivated by? Where is this enzyme found?

2. Administration?

2. FUDR is administered directly into the ___ via? What is this for treatment of?

Inhibition of pyrimidine nucleotide synthesis:

1. MEtabolized by the liver. In activated by dihydropyrimidine dehydrogenase (DPD) found in liver and intestinal mucosa

2. IV --> NO ORAL; long continuous infusion

3. FUDR directly to liver via infusion pump for treatment of metastatic colon carcinoma

37

Inhibition of pyrimidine nucleotide synthesis:

1. Toxicity of intensive doses and/or combinations with leucovorin?

Mechanism of resistance:

2. Loss of ____ for activation of 5FU

3. Amplification of? or mutation to a form not inhibited by ___

Inhibition of pyrimidine nucleotide synthesis:

1. Toxicity: GI, myelosuppression, hyperpigmentation, rash (the previous 2 can be lessened with administration of Vitamin B6), and rare cerebellar toxicity

Resistance:

2. Loss of enzymes for 5FU activation

3. Amplification of thymidylate synthase or mutation to a form not inhibited by FdUMP

38

Inhibition of pyrimidine nucleotide synthesis:

Other actions of 5FU neuclotides:

1. Inhibition of ____ processing or incorporation into ___.

2. Hand foot syndrome presentation? Can be caused by?

Inhibition of pyrimidine nucleotide synthesis:

1. Inhibition of RNA processing and DNA incorporation

2. HFS: erythematous, buring, tender lesions on palms and soles; caused by cytarabine (Ara-C), 5FU, doxorubicin, and methotrexate

39

Cytosine Arabinoside:

1. Most important antimetabolite for therapy of?

2. Analog of?

3. Taken up in the cell via what kind of transport?

 

Cytosine arabinoside:

1. Treatment: Acute Myeloid Leukemia

2. Analog of 2' deoxycytidine

3. Taken up via carrier-mediated nucleoside transport

40

Cytosine arabinoside:

1. What Ara forms are inactive?

2. How are these made active?

3. This is similar to?

Cytosine arabinoside:

1. Ara-U and Ara-UMP are inactive

2. Activated by deoxycytidine kinase

3. Similar to Fludarabine

41

Cytosine arabinoside:

Major effect:

1. Incorporated into DNA and inhibits what 2 things?

2. Ara-CTP inhibits?

3. In what phase Ara-CTP be incorporated?

Cytosine arabinoside:

Major effect:

1. Inhibits template function and chain elongation

2. Ara-CTP inhibits DNA polymerase

3. Only during S phase

42

Cytosine arabinoside:

1. Administration?

2. Why this route of administration?

3. Toxicity? High doses?

4. Main mechanism of resistance?

Cytosine arabinoside:

1. IV

2. IV only because GI mucosa has high levels of cytidine deaminase which converts Ara-C to Ara-U which is inactive

3. Toxicity: myelosupression, N/V, stomatitis; high doses - cerebellar and hepatic toxicity

4. Resistance due to cytidine deaminase inactivating Ara-C

43

Gemcitabine:

MOA:

1. Difluoro analog of _____ (similar to ____)

2. Uptake via?

3. The active forms are?

Gemcitabine:

MOA:

1. Analog of deoxycytidine (similar to Ara-C)

2. Uptake via membrane nucleoside transporter

3. Active forms: gemcitabine diphosphate and gemcitabine triphosphate

44

Gemcitabine:

MOA:

1. Gemcitabine diphosphate inhibits? What does this induce?

2. Depletion of ___ also stimulates gemcitabine phosphorylation and enhances? What does this lead to?

Gemcitabine:

MOA:

1. dFdCDP inhibits RR inducing a depletion of deoxynucleotides

2. Depletion of dCTP enhances incorporation of gemcitabine nucleotides into DNA leading to strand termination

45

Gemcitabine:

MOA:

Gemcitabine triphosphate mediated inhibition of ___ ___ is responsible for long half life which explains the good activity of gemcitabine in ____ tumors.

Gemcitabine:

MOA:

dFdCTP mediated inhibition of dCMP deaminase is responsible for long half live which explains the good activity of gemcitabine in solid tumors

46

Gemcitabine:

1. Administration?

2. Deactivated where? How?

3. Toxicity?

4. Improved overall survival with the addition of what? For?

Gemcitabine:

1. IV

2. Deactivated in liver by deamination to inactive metabolite

3. Tox: myelosupression, flu-like syndrome, asthenia, and mild elevation in liver transaminases

4. Improved survival with the addition of radiation therapy for localized unrescetable pancreatic cancer

47

Hydroxyurea:

MOA:

Inhibits ___ ___ and thus blocks the conversion of _____ diphosphates to ____. This decreased the ____ pool available for DNA synthesis and _____. It also causes cell cycle arrest at/near __/__ boundary and has synergistic toxicity with ____. 

Hydroxyurea:

MOA:

Inhibits ribonucleotide reductase and blocks conversion of ribonucleotide diphosphates to deoxyribonucleotide. This decreases the deoxynucleotide pool available for DNA synthesis and repair. It also causes cell cycle arrest at/near G1/S boundary and has synergistic toxicity with irradiation

48

Hydroxyurea:

MOA:

Accelerates loss of extra-_____ amplified genes present in double minute ( ____ manifestations of gene ____. Thy lack ___ and often harbor genes that provide cancer a selective advantage by coding for ___ that contribute to __-____ ____) chromosomes in response to ____ therapy.

Hydroxyurea:

MOA:

Accelerates loss of extra-chromosomally amplified genes present in double minute (cytogenic manifestations of gene amplification. They lack centromeres and have genes for cancer advantage by coding for proteins that contribute to multi-drug resistance) chromosomes in response to methotrexate therapy

49

Hydroxyurea:

1. Administration? Modify dose in what patients?

2. Primary Toxicity? 

3. Other toxicity?

4. Resistance: increased synthesis of hRRM2 subunit of ribonucleoside diphosphate reductase thus?

Hydroxyurea:

1. Oral; modify in abnormal renal function

2. Primary tox: hematopoietic depression, leukopenia, megaloblastic anemia, and occasionally thrombocytopenia

3. Other: GI, desquamative interstitial pneumonitis, and mild dermatologic reactions

4. Increased hRRM2: restores enzyme activity