Antimetabolites (Antineoplastics II) - Fitz

Question 1

What are the four antineoplastics that are natural products and consequently increase P-glycoprotein expression?

Answer 1

1. Vincristine
2. Paclitaxel
3. Doxorubicin
4. Etoposide

Question 2

Long term use of what drug causes CHF?

Answer 2

Doxorubicin

Question 3

What antineoplastic causes hemorrhagic cystitis?

Answer 3

Cyclophosphamide

Question 4

What drug reverses hemorrhagic cystitis caused by an antineoplastic drug?

Answer 4

MESNA

Question 5

What drug causes BOTH renal toxicity and ototoxicity?

Answer 5

Cisplatin

Question 6

What two antineoplastics cause neurotoxicity?

Answer 6

Vincristine & Paclitaxel

Question 7

What antineoplastic drug prevents DNA synthesis category, but is not actually an antimetabolite?

Answer 7

Hydroxyurea

Question 8

Why is it important to monitor serum Methotrexate levels during the initial course of drug treatment?

Answer 8

High Methotrexate levels in the blood require additional Leucovorin rescue.

Question 9

When a patient does not respond to antineoplastic drug therapy, what things should you be concerned about?

Answer 9

1. Resistance
2. Decreased activation
3. Inherited deficiency of the metabolic enzyme (how drug is eliminated, increased toxicity if drug not eliminated)

Question 10

What drug that we need to know causes Tumor Lysis Syndrome?

Answer 10

6-mercaptopurine

Question 11

What are you going to do if a patient being treated with 6-mercaptopurine develops Tumor Lysis Syndrome?

Answer 11

Give Allopurinol! (excess uric acid)

Decrease dose of 6-MP (by 25%)

Question 12

What are the two groups/mechanisms of drugs that prevent DNA synthesis?

Answer 12

1. Nucleotide synthesis inhibitors
   
   1. blocking production of nucleotides
2. Inhibitors of DNA synthesizing enzymes
   
   1. inhibit DNA polymerase

Question 13

What are the three folic acid analogues that are nucleotide synthesis inhibitors?

Answer 13

1. Methotrexate
2. Pemetrexed
3. Pralatrexate

Question 14

What is the MOA of folic acid analogues? Differences in the three drugs?

Answer 14

competitive inhibitors of DHFR

• MTX blocks DHFR more, and Thymidylate Synthase less
• P drugs block DHFR less, and TS more

Question 15

What are possible forms of resistance to folate analogues?

Answer 15

• Change target enzyme
  
  • decrease DHFR affinity for MTX
• increase DHFR expression
• decrease polyglutamination
• decrease accumulation of drug by decreasing transport
  
  • decrease expression of Reduced Folate Carrier

Question 16

What is unique about the pharmacokinetics of folate analogues?

Answer 16

• Have to use transport systems that are used by a cell to bring folate in
  
  • increased sensitivity in cells/tissues where folate receptor is increased
  • increased resistance where Reduced Folate Carrier expression is reduced

Question 17

How are folate analogues administered?

Answer 17

• MTX can be given orally for non-antineoplastic Tx
• Antineoplastic Tx: given IV or intrathecally to cross BBB

Question 18

How much of folate analogue drug is excreted unchanged in urine? How does this affect patients with altered kidney function?

Answer 18

• Excreted 90% unchanged in urine
  
  • decreased kidney function → severe bone marrow suppression
  • administer with bicarbonate to maintain concentrations appropriately
• Drug interactions: NSAIDs, Cisplatin (nephrotoxic), weak acids (Aspirin)
  
  • alter renal excretion

Question 19

What are the therapeutic uses of folate analogues?

Answer 19

• MTX: extremely broad spectrum antineoplastic
• P drugs: more selective action
  
  • mesothelioma, NSCLC

Question 20

What are the potential cytotoxic side effects of folate analogues?

Answer 20

• primary toxic effects are on bone marrow
• pneumonitis (cough, fever and interstitial infiltrate)
• hepatic fibrosis
• alopecia, dermatitis
• MTX is abortifacaent

Question 21

What is the advantage of Leucovorin Rescue?

Answer 21

• allows use of higher doses of MTX
• decreases toxicity
• shorten treatment term
• decrease chance of resistance

Question 22

When is Leucovorin administration fatal?

Answer 22

When given intrathecally (CNS)

Question 23

What are the two pyrimidine analogues?

Answer 23

1. 5-Fluoruracil
2. Capecitabine

Question 24

What is MOA of pyrimidine analogues?

Answer 24

• 5-FU: inhibits thymidylate synthase
• Capecitabine: converted to 5-FU in cancer cells → inhibits thymidylate synthase
• Cells unable to make dTMP

Question 25

Why is Leucovorin also used in antineoplastic treatment with pyrimidine analogue drugs?

Answer 25

increases binding of 5-FU to thymidylate synthase (increases 5-FU efficacy)

Question 26

What are two potential forms of resistance to pyrimidine analogues?

Answer 26

* changes in target enzymes * increased expression of thymidylate synthase * decreased activation of prodrugs * decreased pyrimidine monophosphate kinase activity

Question 27

What is event is important for 5-FU to function?

Answer 27

* activation of drug * drug must enter pyrimidine synthesis pathway (3 steps) * pyrimidine monophosphate kinase (form of resistance)

Question 28

How are folate analogue antineoplastics eliminated?

Answer 28

* broken down by dihydropyrimidine dehydrogenase * significant metabolic degradation occurs (~80% of the drug is eliminated by hepatic metabolism and 20% by renal excretion) * many other tissues also degrade 5-FU (GI tract, so cannot give drug orally) * inherited deficiency of dihydropyrimidine dehydrogenase leads to greatly increased drug sensitivity (~8% of US population)

Question 29

What are the therapeutic uses of pyrimidine analogues?

Answer 29

* tends not to be particularly effective when given alone - synergistic with METHOTREXATE * colorectal cancer (most widely used drug for this purpose) * ovarian and breast cancer (part of CMF and FAC regimens)

Question 30

What are the possible toxic side effects of pyrimidine analogues?

Answer 30

* 5-FU has a **low** **therapeutic index** (even for an antineoplastic drug) * primary toxic effects are on **bone marrow** * myelosuppression reaches maximum in 9-14 days * **acute cerebellar syndrome** (somnolence, ataxia of trunk or extremities, unsteady gait, slurred speech, nystagmus) * occurs within weeks/months of initiating treatment in 5% of patients * complete recovery following cessation of treatment * alopecia, dermatitis * hand-foot syndrome (palmar-plantar erythrodysesthesia)

Question 31

What two drugs are purine analogues?

Answer 31

1. 6-Mercaptopurine 2. 6-Thioguanine

Question 32

How do 6-MP and 6-TG become activated?

Answer 32

HGRPT in the Salvage Pathway of purine synthesis

Question 33

What enzyme do purine analogues block?

Answer 33

Guanylyl kinase and cause "pseudofeedback inhibition" (GMP builds up)

Question 34

What does the inhibition of guanylyl kinase and "pseudofeedback inhibition" result in?

Answer 34

1. interference with DNA and RNA synthesis 2. inhibition of purine nucleotide interconversion 3. a decrease in intracellular levels of guanine nucleotides (inhibition of glycoprotein synthesis) 4. incorporation of purinethiols into both DNA and RNA, leading to DNA damage

Question 35

What are potential forms of resistance to purine analogues?

Answer 35

* changes in target enzymes * decreased ability to inhibit PNP and HGPRT * decreased activation of prodrugs * decreased expression of activation enzymes (esp. HGPRT) * increased inactivation * increased rates of degradation of the drugs or their "activated" analogues

Question 36

What are possible toxic side effects of purine analogues?

Answer 36

* primary toxic effects are on bone marrow * anorexia, nausea and vomiting occur in 25% of adults; less often in children * as with any drugs used to treat leukemias, can cause TUMOUR LYSIS SYNDROME

Question 37

How are purine analogues administered?

Answer 37

orally

Question 38

What are the two metabolic pathways of 6-MP in the liver? What are "issues" of these systems?

Answer 38

* xanthine oxidase oxidizes 6-MP to 5-thiouric acid, which is inactive * DOSE MUST BE ADJUSTED IF GIVEN WITH ALLOPURINOL (due to TUMOUR LYSIS SYNDROME) * if you are treating the gout with Allopurinol, you must decrease 6-MP dose * methylation and subsequent oxidation * the enzyme responsible (thiopurine methyltransferase) has no known natural function, and polymorphic inheritance; 15% of the UK population has little or no enzyme activity, which causes increased toxicity

Question 39

T/F Unlike 6-MP, 6-TG can be administered concurrently with ALLOPURINOL.

Answer 39

True | (different metabolism)

Question 40

What are the therapeutic uses of purine analogues?

Answer 40

* acute leukemias * 6-TG is synergistic with CYTARABINE

Question 41

What are the four antineoplastic drugs that inhibit DNA synthesizing enzymes?

Answer 41

* PYRIMIDINES: **CYTARABINE (Ara-C)**, **GEMCITABINE** (converted into compounds that compete with/mimic CDP and CTP) * PURINE: **CLADRIBINE**, **FLUDARABINE** (converted into compounds that compete with/mimic ADP and ATP)

Question 42

What is the MOA of DNA synthesizing enzyme inhibitors?

Answer 42

* incorporated into DNA where they block DNA polymerases (α = DNA synthesis and β = DNA repair) * also inhibit ribonucleotide reductase

Question 43

What DNA synthesizing enzyme inhibitor is not considered an Antimetabolite?

Answer 43

Hydroxyurea

Question 44

What are three effects of Cytarabine (Ara-C)?

Answer 44

1. blocks DNA elongation 2. can cause repititions → mutagenic 3. forces differentiation of cells

Question 45

What cause cell apoptosis when treating with Gemcitabine?

Answer 45

DNA strand termination

Question 46

What diseases/conditions is Hydroxyurea used to treat?

Answer 46

* CML * sickle cell anemia * increases production of fetal hemoglobin γ, interfering with the polymerization of HbS, and therefore decreasing painful crises in patients with severe sickle cell disease

Question 47

What is unique about Hydroxyurea?

Answer 47

synchronizes cells in a radiation-sensitive phase of the cell cycle (G1)