Pharm Exam 3: Antimetabolites

Front 1

Name a folic acid analog

Back 1

Methotrexate

Front 2

Name 3 purine analogs

Back 2

1. 6-mercaptopurine
2. 6-thioguanine
3. fludarabine

Front 3

6-mercaptopurine is what kind of antimetabolite?

Back 3

purine analog

Front 4

6-thioguanine is what kind of antimetabolite?

Back 4

purine analog

Front 5

fludarabine is what kind of antimetabolite?

Back 5

purine analog

Front 6

Methotrexate is what kind of antimetabolite?

Back 6

Folic acid analog

Front 7

Name 3 pyrimidine analogs

Back 7

1. 5-Fluorouracil
2. Cytosine arabinoside (ara-c)
3. gemcitabine

Front 8

5-fluorouracil is what kind of antimetabolite?

Back 8

pyrimidine analog

Front 9

cytosine arabinoside (ara-c) is what kind of antimetabolite?

Back 9

pyrimidine analog

Front 10

gemcitabine is what kind of antimetabolite?

Back 10

pyrimidine analog

Front 11

What is the function of hydoxyurea

Back 11

Inhibit ribonucleotide reductase

Front 12

What antimetabolite inhibits ribonucleotide reductase?

Back 12

Hydroxyurea

Front 13

Folic acid analogs, purine analogs, pyrimidine analogs, and hydroxyurea all act as what class of anti-cancer drugs?

Back 13

Antimetabolites

Front 14

Premetrexed is used to treat what kind of cancer?

Back 14

Mesothelioma

Front 15

Are antimetabolites active as given?

Back 15

No, must be activated intracellularly

Front 16

Antimetabolites do/do not have structural similarity to physiological intermediates?

Back 16

Do have structural similarity to physiological intermediates

Front 17

What is the main mechanism of action of antimetabolites?

Back 17

Inhibit de novo synthesis of purine and pyrimidines (nucleotides)

Front 18

What two antimetabolites inhibit phophoribosyl pyrophosphate (PRPP) amidotransferase?

Back 18

1. 6-mercaptopurine
2. 6-thioguanine

Front 19

What enzyme is required for generation of purine ring?

Back 19

Dihydrofolate reductase (DHFR)

Front 20

What two antimetabolites inhibit DHFR?

Back 20

1. MTX (Methotrexate)
2. Trimetrexate (TMQ)

Front 21

IMP gets converted to what two possibilites?

Back 21

1. GMP
2. AMP

These are purines (Adenine and guanine)

Front 22

What drug inhibits the conversion of IMP to AMP and GMP

Back 22

6-mercaptopurine

Front 23

What enzyme is responsible for conversion of IMP --> AMP, GMP?

Back 23

IMP dehydrogenase

Front 24

What drug is most selective against the IMP dehydrogenase enzyme?

Back 24

6-TG

Front 25

What two other drugs besides 6-TG inhibit IMP dehydrogenase preventing IMP --> AMP, GMP?

Back 25

6-MP and tiazofurin

Front 26

What enzyme converts ADP, GDP --> dADP, dGDP?

Back 26

Ribonucleotide reductase

Front 27

What two drugs inhibit ribonucleotide reductase?

Back 27

Hydroxyurea and fludarabine (purine analog)

Front 28

Which is more lipid soluble (MTX or TMQ)?

Back 28

TMQ = trimetrexate

Front 29

Which antifolate is multitargeted? (MTX, TMQ, or pemetrexed)

Back 29

Pemetrexed

Front 30

What is an essential dietary factor required for synthesis of DNA precursors (thymidylate and purines) and RNA (purines)?

Back 30

Folic acid

Front 31

For which drug is the primary mechanism of action inhibition of DHFR?

Back 31

Methotrexate (MTX)

Front 32

Which drug depletes THF cofactors required for synthesis of thymidylate and purines?

Back 32

Methotrexate (MTX)

Front 33

Does MTX require a specific transporter to enter the cell? If so, which one?

Back 33

Yes - Reduced folate transporter

Front 34

Polyglutamation is a conversion that occurs. This does/does not inhibit other folate-requiring enzymes for thymidylate and purine synthesis?

Back 34

Does inhibit other folate-requiring enzymes for thymidylate and purine synthesis

Front 35

Polyglutamation increases/decreases the affinity of MTX for thymidylate synthetase

Back 35

Increases the affiinity of MTX for thymidylate synthetase

Front 36

Polyglutamation allows/prevents egress of MTX from the cell?

Back 36

Prevents egress of MTX from the cell

Front 37

Is a transport protein required for TMQ (trimetrexate)?

Back 37

No - TMQ is more lipid soluble and does not need a transport protein

Front 38

Does MTX require a transport protein

Back 38

Yes MTX requires a transport protein

Front 39

If you encounter a patient with folate transport protein deficient resistant cancer, which folate analog should be given?

Back 39

Trimetrexate (TMQ) because it is more lipid soluble and does not need a transport protein

Front 40

MTX also activates p53, cell cycle arrest and apoptosis (T/F)

Back 40

True

Front 41

Why is leucovorin given to patient on MTX?

Back 41

To alleviate BM suppression

Front 42

5-formyl-tetrahydrofolate is also known as what trade name?

Back 42

Leucovorin

Front 43

What drug can rescue the cell from MTX cytotoxicity?

Back 43

Leucovorin (5-formyl-tetrahydrofolate)

Front 44

Is MTX toxic to all rapidly dividing cells?

Back 44

Yes, MTX is toxic to all rapidly dividing cells

Front 45

MTX kills cells in which phase of the cell cycle?

Back 45

S phase

Front 46

MTX is more effective in slower/more rapid proliferating tumors?

Back 46

Rapidly proliferating tumors

Front 47

Coadministered drugs that displace MTX from serum albumin can increase/decrease toxicity?

Back 47

Increase toxicity
ASA and penicillins. Probenecid blocks organic acid transport = interfere also

Front 48

ASA, sulfonamides, and penicillins are protein bound and can have what effect when given with MTX?

Back 48

Displace MTX from serum albumin and increase MTX toxicity

Front 49

Ascites and pleural effusions are/are not contraindications to MTX?

Back 49

Are contraindications. MTX can leak out b/c it gains access to third space

Front 50

MTX is metabolized by liver or kidney?

Back 50

Kidney, as salt of weak acid
ASA and penicillin also excreted this way - can interfere
Probenecid blocks organic acid transport system - interferes

Front 51

What is the main toxicity associated with MTX?

Back 51

Myelosuppression

Front 52

What drug is used to treat ALL in children?

Back 52

MTX

Front 53

What drug is used in high-dose as adjuvant to treat osteogenic sarcoma?

Back 53

MTX

Front 54

What drug is also used to treat psoriasis, rheumatoid arthritis, and for immunosuppression?

Back 54

MTX

Front 55

Which purine analog is the analog of hypoxanthine?

Back 55

6-mercaptopurine

Front 56

Which purine analog is the analog of guanine?

Back 56

6-thioguanine

Front 57

Nucleotides form from 6-MP and 6-TG inhibits de novo purine synthesis (inhibits PRPP amidoTFase) and does/does not become incorporated into nucleic acids?

Back 57

Does also become incorporated into nucleic acids

Front 58

6-MP and 6-TG + PRPP are catalyzed by what enzyme?

Back 58

HGPRT (hypoxanthine-guanine phosphoribosyltransferase)

Front 59

T-IMP and 6-thioGMP can/cannot be incorporated into DNA

Back 59

Can be incorporated into DNA

Front 60

T-IMP and 6-thioGMP are formed from what enzyme?

Back 60

HGPRT (hypoxanthine guanine phosphoribosyl transferase)

Front 61

T-IMP is a good/poor substrate for guanylyl kinase?

Back 61

T-IMP is a poor substrate for guanylyl kinase. Leads to accumulation of T-IMP accumulation in cells and negative feedback inhibition of PRPP amidotransferase (first step in de novo synthesis)

Front 62

What enzyme is involved in the first step of de novo purine synthesis?

Back 62

PRPP amidotransferase

Front 63

T-IMP accumulation results in what effect of PRPP amidotransferase?

Back 63

Negative feedback inhibition of PRPP amidotransferase (first step in de novo synthesis)

Front 64

Negative feedback inhibition of PRPP amidotransferase caused by accumulation of T-IMP is the most important effect for what drug?

Back 64

6-mercaptopurine

Front 65

Tumor cell lysis syndrome can occur when given 6-MP. What drug can be given to alleviate this?

Back 65

Allopurinol (xanthine oxidase inhibitor)

Front 66

If you give a patient allopurinol (xanthine oxidase inhibitor) what adjustment must be made to the oral dose of 6-MP?

Back 66

Reduce the oral dose b 75% to decrease the risk of toxicity

Front 67

Elimination of 6-MP and 6-TG is renal or hepatic?

Back 67

Hepatic b/c orally active (PO) and 6-MP is extensively metabolized by Xanthine Oxidase
This can lead to hyperuricemia (Tumor Lysis syndrome)
Prevent with Allopurinol (XO inhibitor) + reduced dose of 6-MP by 75%

Front 68

If there is increased activity of MRP5, what happens to the drug?

Back 68

Increased efflux of the drug = resistance to the drug

Front 69

The active triphosphate form of fludarabine inhibits DNA Pol alpha, ribonucleotide reductase, DNA primase, and DNA ligase resulting in inhibition of what?

Back 69

DNA and RNA synthesis

Front 70

If active triphosphate form of fludarabine is incorporated into DNA, what happens?

Back 70

Chain termination

Front 71

Active triphosphate form of fludarabine inhibits RNA processing and mRNA translation (T/F)

Back 71

True

Front 72

For which purine metabolite is the major effect through the activation of apoptosis?

Back 72

Fludarabine

Front 73

Fludarabine is available PO or IV?

Back 73

IV

Front 74

6-MP and 6-TG are usually given PO or IV?

Back 74

PO

Front 75

Renal clearance represents how much % of total body clearance?

Back 75

40%

Front 76

What is the main toxicity associated with fludarabine?

Back 76

Myelosuppression

Front 77

Which drug is mainly used for treatment of CLL?

Back 77

Fludarabine (converted to active triphosphate form intracellularly)

Front 78

What enzyme phosphorylates fludarabine to give active triphosphate form of fludarabine?

Back 78

deoxycytidine kinase

Front 79

What is the most frequently targeted step in treatment with pyrimidine analog?

Back 79

Conversion of dUMP to TMP

Front 80

Name a unique substrate for DNA synthesis

Back 80

TMP

Front 81

What enzyme catalyzes the conversion of dUMP to TMP?

Back 81

thymidylate synthase

Front 82

What enzyme does 5-fluorouracil and FUdR inhibit?

Back 82

thymidylate synthase

Front 83

Reduced production of TTP causes enhanced incorporation of what into DNA?

Back 83

dUTP

Front 84

Conversion of UDP and CDP to dUDP and dCDP is catalyzed by what enzyme?

Back 84

Ribonucleotide reductase (which is inhibited by Hydroxyurea)

Front 85

What drug inhibits the incorporation of dCTP into DNA by DNA polymerase?

Back 85

Ara-C

Front 86

What drug is important for the treatment of colon cancer?

Back 86

5-FU

Front 87

What drug mimics uracil biochemically?

Back 87

5-FU

Front 88

Do you need THF for FdUMP to bind tightly to thymidylate synthetase?

Back 88

yes, THF is needed

Front 89

What is the metabolism of 5-FU?

Back 89

Liver

Front 90

What is the route of administration of 5-FU?

Back 90

IV

Front 91

Long continuous infusions or rapid IV injections of 5-FU are better?

Back 91

Long continuous infusions

Front 92

FUdR is administered directly into the liver via infusion pump to treat what cancer and metastasis?

Back 92

Colon cancer and liver metastasis

Front 93

What drug is used to treat liver mets from colon cancer?

Back 93

FUdR

Front 94

What enzyme is found in the liver that inactivates 5-FU

Back 94

dihydropyrimidine dehydrogenase

Front 95

Why is leucovorin given with 5-FU?

Back 95

To enhance cytotoxicity

Front 96

If cancer cells have insufficient levels of 5-10 methylene tetrahydrofolate, what drug can be give with 5-FU to enhance cytotoxicity?

Back 96

Leucovorin

Front 97

Gi toxicity, myelosuppression, skin hyperpigmentation and rashes are adverse reactions of what drug?

Back 97

5-FU

Front 98

What can be given along with 5-FU to lessen adverse side effects?

Back 98

Pyridoxine (Vitamin B6)

Front 99

Is 5-FU a radiation sensitizer?

Back 99

Yes it is

Front 100

Cytosine arabinoside is also known by what name?

Back 100

Ara-C

Front 101

What is the most important antimetabolite used in AML therapy?

Back 101

Ara-C (cytosine arabinoside)

Front 102

What is the most effective agent for induction of remission of AML?

Back 102

Ara-C (cytosine arabinoside)

Front 103

What anti-metabolite is incorporated into DNA and inhibits template function and chain elongation?

Back 103

Ara-C

Front 104

What drug inhibits DNA polymerase

Back 104

Ara-C
Fludarabine (-)s DNA Pol alpha

Front 105

Cells not in S phase will/will not be affected by Ara-C

Back 105

Will not be affected by Ara-C

Front 106

There are high levels of cytdine deaminase in GI mucosa. How does this affect the route of administration of Ara-C?

Back 106

Must be given IV

Front 107

Increased synthesis and retention of Ara-CTP is associated with longer/shorter duration of complete remission in AML?

Back 107

Longer duration of remission of AML

Front 108

What is the difluoro analog of deoxycytidine?

Back 108

Gemcitabine

Front 109

Is the diphosphate form of gemcitabine active?

Back 109

Yes both di and triphosphate forms of gemcitabine are active

Front 110

What enzyme does dFdCDP inhibit?

Back 110

dFdCDP inhibits ribonucleotide reductase --> depletion of pool of deoxynucleotides (dNTP)

Front 111

Incorporation of gemcitabine nucleotides into DNA leads to what?

Back 111

Strand termination

Front 112

Can gemcitabine enhance its own activity?

Back 112

Yes. Inhibits dCMP deaminase and prolongs the cellular halflife of active dFdCTP - explains the good activity of Gemcitabine in solid tumors

Front 113

What drug has good activity in solid tumors?

Back 113

Gemcitabine.
dFdCTP-mediated inhibition of dCMP deaminase = prolong cellular T1/2 of active dFdCTP = explains good activity of Gemcitabine in solid tumors

Front 114

What is the major toxicity of gemcitabine?

Back 114

Myelosuppression

Front 115

Gemcitabine is a radiosensitizer (T/F)

Back 115

True. Do not use w/ radiation

Front 116

Gemcitabine should/should not be used with radiotherapy?

Back 116

Should not - it is a potent radiosensitizer

Front 117

Hydroxyurea causes cell cycle arrest at what junction of the cell cycle?

Back 117

G1/S phase boundary

Front 118

What enzyme deoxifies ribonucleotides

Back 118

ribonucleotide reductase

Front 119

HU does/does not have synergistic toxicity with irradiation?

Back 119

Does have synergistic effects - cells more sensitive to irradiation

Front 120

What antimetabolite has the least myelosuppresion?

Back 120

Hydroxyurea

Front 121

hRRM2 subunit of ribonucleoside diphosphate reductase can be regenerated to restore enzyme activity T/F?

Back 121

True - resistance to Hydroxyurea mechanism

Front 122

6-MP + PRPP catalyzed by HGPRT gives what product?

Back 122

T-IMP

Front 123

6-TG + PRPP catalyzed by HGPRT gives what product

Back 123

6-thioGMP

Front 124

Between T-IMP and 6-thioGMP, which is the more prevalent product?

Back 124

6-thioGMP

Front 125

More 6-thioGMP or T-IMP is converted and incorporated into RNA and DNA?

Back 125

6-thioGMP

Front 126

Instead of being incorporated into DNA, 6-MP + PRPP catalyzed by HGPRT forms T-IMP which has what function?

Back 126

Accumulates in cells leading to feedback inhibition of PRPP amidoTFase (first step in de novo synthesis)

Front 127

What is the first step in de novo purine synthesis?

Back 127

PRPP amidoTFase

Front 128

T-IMP is a good/poor substrate for guanylyl kinase?

Back 128

Poor substrate for guanylyl kinase