Cancer III - Antimetabolites

Question 1

Antimetabolite Drugs:

1. Folic acid analogs?
2. Purine analogs?

Answer 1

Antimetabolite Drugs:

1. Folic acid analogs = methotrexate
2. Purine analogs = 6-mercaptopurine, 6-thioguanine, and fludarabine

Question 2

Antimetabolite Drugs:

1. Pyrimidine analogs?
2. One other drug?

Answer 2

Antimetabolite Drugs:

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

Question 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?

Answer 3

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

Question 4

Purines and Pyrimadines:

1. Which is a single ring? Double?
2. Which bases are purines?
3. Which are pyrimidines?

Answer 4

Purines and Pyrimadines:

1. Single ring = pyrimidine; double = purine
2. Purines = Adenine and guanine
3. Pyrimidines = cytosine, thymine, and uracil

Question 5

Inhibition of purine nucleotide synthesis:

1. Which drugs?
2. What do they inhibit?

Answer 5

Inhibition of purine nucleotide synthesis:

1. 6-mercaptopurine and 6-thioguanine
2. Inhibit phosphoribosyl pyrophosphate (PRPP) aminotransferase

Question 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?

Answer 6

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

Question 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?

Answer 7

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

Question 8

Folic Acid analogs:

Name 3 drugs.

Answer 8

Inhibition of purine nucleotide synthesis:

a. methotrexate
b. trimetrexate
c. pemetrexed

Question 9

Methotrexate:

1. Normal function of folic acid?
2. Primary MOA?

Answer 9

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

Question 10

Methotrexate:

1. Requires what?
2. Undergoes conversion to a series of ______ which also inhibits other?
3. Polyglutamation increases _____ of methotrexate for ____ ____ and prevents?

Answer 10

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

Question 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?

Answer 11

Methotrexate:

1. Leucovorcin (folinic acid) for OD
2. TS and AICAR: FH2(Glun)
3. TH and GAR: 10-CHO-FH2 (Glun)

Question 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?

Answer 12

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

Question 13

Methotrexate:

1. What can rescue the cell from the cytotoxicity of methotrexate?
2. What phase is methotrexate active in?

Answer 13

Methotrexate:

1. 5-formyl-THF (leucovorin) can rescue cell from cytotox
2. Active in S phase –> effective in rapidly proliferating tumors

Question 14

Methotrexate:

Absorption/Fate/Excretion:

1. Protein binding relevance?
2. Volume of distribution? Thus, what are contraindications?
3. Used caustion in patients with impaired?

Answer 14

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

Question 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?

Answer 15

Methotrexate:

1. Excreted by the kidney as a salt of a weak acid. Aspirin 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

Question 16

Methotrexate:

1. Standard dose toxicity?
2. High dose toxicity?

Answer 16

Methotrexate:

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

Question 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 _____ ____

Answer 17

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

Question 18

Methotrexate:

Mechanisms of resistance:

1. Decreased synthesis of methotrexate ______
2. Increased expression of drug ____ _____

Answer 18

Methotrexate:

Mechanisms of resistance:

1. Decreased synthesis of methotrexate polyglutamates
2. Increased expression of drug efflux transporter

Question 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?

Answer 19

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

Question 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?

Answer 20

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

Question 21

Purine analogs:

1. What generates the purine ring?
2. What is this inhibited by?

Answer 21

Purine analogs:

1. Purine ring is generated by DHF reductase
2. Inhibited by methotrexate and trimetrexate

Question 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?

Answer 22

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

Question 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?

Answer 23

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

Question 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?

Answer 24

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

Question 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 \_\_\_\_.

Answer 25

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_

Question 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?

Answer 26

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_

Question 27

Fludarabine: 1. MOA? 2. It is a prodrug _____ intracellularly by _____ kinase. 3. The metabolite inhibits? Ultimate result?

Answer 27

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

Question 28

Fludarabine: 1. Causes ____ \_\_\_\_ when incorporated into DNA 2. Inhibits RNA _____ and ___ \_\_\_\_\_\_\_ when incorporated into RNA 3. Major effect is activation of \_\_\_\_

Answer 28

Fludarabine: 1. Causes _chain termination_ when incorporated into DNA 2. Inhibits RNA _processing_ and _mRNA translation_ 3. Activation of _apoptosis_

Question 29

Fludarabine: 1. Route of administration? 2. Patients with compromised ____ function should be treated with caution. Why? 3. Primary use?

Answer 29

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)

Question 30

Fludarabine: 1. Toxicity? 2. Resistance is due to decreased activity of ____ \_\_\_. How does this normally function?

Answer 30

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

Question 31

Inhibition of pyrimidine nucleotide synthesis: 1. Most frequently targeted step is conversion of ____ to ____ by ____ \_\_\_. 2. What two drugs inhibit the above?

Answer 31

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_

Question 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 \_\_\_\_

Answer 32

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_

Question 33

Inhibition of pyrimidine nucleotide synthesis: What are the pyrimidine analogs?

Answer 33

Inhibition of pyrimidine nucleotide synthesis: a. 5 fluorouracil (5FU) b. FUDR c. FTORAFUR

Question 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?

Answer 34

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_

Question 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 \_\_\_

Answer 35

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_

Question 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?

Answer 36

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_

Question 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 \_\_\_

Answer 37

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_

Question 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?

Answer 38

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

Question 39

Cytosine Arabinoside: 1. Most important antimetabolite for therapy of? 2. Analog of? 3. Taken up in the cell via what kind of transport?

Answer 39

Cytosine arabinoside: 1. Treatment: _Acute Myeloid Leukemia_ 2. Analog of _2' deoxycytidine_ 3. Taken up via _carrier-mediated nucleoside_ transport

Question 40

Cytosine arabinoside: 1. What Ara forms are inactive? 2. How are these made active? 3. This is similar to?

Answer 40

Cytosine arabinoside: 1. Ara-U and Ara-UMP are inactive 2. Activated by deoxycytidine kinase 3. Similar to Fludarabine

Question 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?

Answer 41

Cytosine arabinoside: Major effect: 1. _Inhibits template function and chain elongation_ 2. Ara-CTP _inhibits DNA polymerase_ 3. Only during S phase

Question 42

Cytosine arabinoside: 1. Administration? 2. Why this route of administration? 3. Toxicity? High doses? 4. Main mechanism of resistance?

Answer 42

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

Question 43

Gemcitabine: MOA: 1. Difluoro analog of _____ (similar to \_\_\_\_) 2. Uptake via? 3. The active forms are?

Answer 43

Gemcitabine: MOA: 1. Analog of _deoxycytidine_ (similar to _Ara-C)_ 2. Uptake via membrane nucleoside transporter 3. Active forms: gemcitabine diphosphate and gemcitabine triphosphate

Question 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?

Answer 44

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

Question 45

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

Answer 45

Gemcitabine: MOA: dFdCTP mediated inhibition of _dCMP deaminase_ is responsible for long half live which explains the good activity of gemcitabine in _solid_ tumors

Question 46

Gemcitabine: 1. Administration? 2. Deactivated where? How? 3. Toxicity? 4. Improved overall survival with the addition of what? For?

Answer 46

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_

Question 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 \_\_\_\_.

Answer 47

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_

Question 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.

Answer 48

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

Question 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?

Answer 49

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