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Cology 2 Exam 4 > Antineoplastic therapy - Antimetabolites > Flashcards

Antineoplastic therapy - Antimetabolites Flashcards

1
Q

Name the folic acid analogs

A

Methotrexate
Trimetrexate
Pemetrexed
Pralatrexate (T cell lymphoma)

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2
Q

Name the pyrimidine analogs

A 
5-Fluorouracil
Floxuridine
Capecitabine
5-Azacitidine
Cytarabine
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3
Q

Name the purine analogs

A 
Mercaptopurine
Fludarabine
Cladribine
Thioguanine
Pentostatin 
Clofarabine
Nelarabine
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4
Q

Describe antimetabolites as a whole group

A

All are structural analogs of naturally occurring bases or intermediates

They inhibit enzymes or substitute for naturally occurring purines/pyrimidines

They have cytotoxic effects during S phase and impaired nucleotide synthesis in G1

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5
Q

What causes resistance in antimetabolites?

A

Gene amplification of enzymes that are inhibited

Production of target enzymes with less affinity for the drug

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6
Q

Which drug produced the first (temporary) remission of Leukemia?

A

Methotrexate

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7
Q

Which drug produced the first cure of a solid tumor?

A

Methotrexate

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8
Q

Besides cancer, what else is Methotrexate used for?

A

Immunosuppressant in rheumatoid arthritis, lupus, and transplants

It inhibits cell-mediated immune reactions, so you use low doses in the things listed above

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9
Q

What is the MOA of Methotrexate?

A

It is an analog for folic acid so it competes for dihydrofolate reductase, which is an enzyme that converts dihydrofolate to tetrahydrofolate

This reaction is responsible for the transfer of carbon groups in synthesis of THYMIDINE, CYSTEINE, and METHIONINE

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10
Q

Describe the pharmacokinetics of Methotrexate

A

It is actively transported into the cell (cancer cells more than normal cells!)

MTX is reduced in the cells to trap them (polyglutamate synthetase adds glutamyl residues)

Pralatrexate and pemetrexed the residues are added faster to lock into the cell

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11
Q

Does Methotrexate have a rescue

A

Yes - Leucovorin rescue

Leucovorin is converted into N5N10-methylene-FH4 in normal cells (ie bone marrow, kidney) to reduce the side effects

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12
Q

How is Methotrexate administered?

A

Oral, IV

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13
Q

Indications for Methotrexate

A

ALL in children (limited value in adults)

Choriocarcinoma, breast, head and neck, bladder, trophoblastic tumor in women, osteosarcoma, CNS lymphomas

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14
Q

Adverse effects of Methotrexate?

A

GI and oral epithelial ulceration (sores in mouth)

Bone marrow suppression

Nausea, vomiting, diarrhea, hepatotoxicity, alopecia

Teratogenic!!! It’s been used with Misoprostol as abortifacient

Must monitor renal function bc it is actively secreted into the proximal tubule

MULTIPLE BLACK BOX WARNINGS: Hepatic disease, pregnancy, pulmonary disease, infections (bc suppresses immune system)

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15
Q

Describe the MOA of Pemetrexed

A

Converted to poly-glutamated form, rapidly transported, inhibits BOTH thymidylate synthase and dihydrofolate reductase

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16
Q

Indications for Pemetrexed

A

It has activity against mesothelioma, non-small cell lung cancer

It’s better than methotrexate in colon cancer

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17
Q

Toxicities for Pemetrexed

A

Similar to MTX

Rash in 40% of patients, skin reactions
SEVERE bone marrow suppression, GI
Neuropathy

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18
Q

Describe the structure of 5-Fluorouracil

A

Uracil with a fluorine in position 5 of the uracil ring

It is attached to ribose/deoxyribose to form fdUMP

Precursor to thymidine!

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19
Q

Describe the structure of Cytarabine

A

Cytosine analog in which natural ribose is replaced by D-arabinose

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20
Q

How do pyrimidine analogs work?

A

They are activated by tumor cell enzymes, decrease the activity of DNA polymerase (?) and are incorporated into DNA

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21
Q

Describe the MOA of 5-fluorouracil

A

5-FU is attached to ribose/deoxyribose to form fdUMP

fdUMP competes with dUMP to inhibit thymidine synthetase, reducing thymidine production for DNA synthesis and RNA synthesis.

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22
Q

Does 5-fluorouracil have a rescue?

A

NO.

Leucovorin POTENTIATES toxicity of 5-FU in cancer cells lacking tetrahydrofolate

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23
Q

How is 5-fluorouracil administered?

A

IV and Topical
Short half life
Infused over 5 days to get cells in S phase bc it is cell cycle specific

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24
Q

Indications for 5-fluorouracil?

A

Slow growing, solid tumors (breast, stomach, esophageal, pancreas, head, and neck)

Topical - premalignant skin lesions

25
Q

What is Floxuridine?

A

FUdR (FU + deoxyribose)

Given via hepatic artery infusion

Used for metastatic colon carcinoma in the liver, liver cancer

26
Q

What is Capecitabine?

A

Prodrug of FUdR - used for non responsive metastatic breast cancer, metastatic colorectal cancer

27
Q

Toxicities of 5-Fluorouracil?

A 
Nausea, vomiting, diarrhea
Myelosuppression
Alopecia
Mucosal damage (oral and GI)
Hepatotoxicity
Hand-food syndrome (pain and sensitivity in palms and soles, more frequently with Capecitabine and Floxuridine tho)
28
Q

What is Cytarabine?

A

Cytosine plus D-arabinose sugar

29
Q

What is the MOA of Cytarabine?

A

Inhibits DNA polymerase, you have unbalanced growth (one strand is affected, the other isn’t) - so it’s cytotoxic

It’s incorporated into the DNA and the arabinose sugar inhibits elongation

30
Q

How is Cytarabine administered?

A

IV over 5-7 days to phase cell cycle

31
Q

Indications of Cytarabine?

A

Acute myelogenous leukemia (most effective)

Also chronic myelogenous leukemia, acute lymphocytic leukemia, meningeal leukemia, and non-Hodgkin’s lymphoma

32
Q

Toxicities of Cytarabine?

A

Moderate nausea, vomiting, diarrhea, stomatitis

CEREBELLAR TOXICITY (ataxia, seizures, slurred speech) after intrathecal administration

Potent myelosuppression

Oral and GI ulcerations, hepatotoxicity

Dyspnea, fever, pulmonary fibrosis

33
Q

What is Gemcitabine?

A

Difluoroanalogue of cytidine incorporated into DNA, terminates the strand and increases apoptosis

NOT S PHASE SPECIFIC!!!!!

34
Q

How is Gemcitabine administered?

A

IV on days 1, 8, and 15 of a 28 day cycle

35
Q

Indications for gemcitabine?

A

Metastatic pancreatic, lung, ovarian, bladder cancer

36
Q

Toxicities for gemcitabine?

A

Myelosuppression, hepatotoxicity, flu-like syndrome, potent radiation sensitizer, dyspnea

37
Q

What is 6-mercaptopurine?

A

Thio analog of hypoxanthine, converted into nucleotides, inhibit DNA synthesis

38
Q

What is Thioguanine?

A

Thio analog of guanine

39
Q

What is Fludarabine?

A

Fluorinated adenosine arabinose, inhibtits DNA polymerase

40
Q

What is Cladribine?

A

(2-chlorodeoxyadenosine)

Inhibits DNA polymerase

41
Q

What is Clofarabine?

A

2 chloro 2 fluoroarabinosyladenine

Inhibits DNA polymerase

42
Q

What is Nelarabine?

A

6-methoxy-arabinosyl guanine

Inhibits DNA polymerase

43
Q

What is the MOA of 6-mercaptopurine?

A

6-MP is phosphorylated and added to sugar to form thio-IMP
It is a substrate for hypoxanthine-guanine phosphoribosyl transferase

It inhibits adenosine and xanthine formation

This prevents DNA synthesis, and can also be incorporated into RNA

44
Q

How is 6-mercaptopurine administered?

A

Oral and IV

45
Q

Indications for 6-mercaptopurine?

A

Acute lymphocytic leukemia (ALL)

Acute and chronic myelogenous leukemia (AML, CML)

46
Q

How is 6-mercaptopurine metabolized?

A

P-450

Xanthine oxidase - purines into uric acid - hyperuricemia, hyperuricosuria

47
Q

Does 6-mercaptopurine have a rescue?

A

Yes - allopurinol can be given to increase 6 MP levels and decrease uric acid levels
This can increase the drug concentrations without increasing the dose

48
Q

Toxicities with 6-mercaptopurine?

A 
Bone marrow suppression
Hematological toxicity, bleeding
Nausea, vomiting, anorexia
Long term hepatotoxicity
Opportunistic infections
49
Q

Indications for thioguanine?

A

Acute myoblastic and lymphoblastic leukemia (AML, ALL)

50
Q

Toxicities for thioguanine?

A

Hematological suppression
Bleeding
GI effects

51
Q

MOA for Fludarabine?

A

It’s incorporated into DNA, terminates the chain

52
Q

Indications for Fludarabine?

A

Acute and chronic lymphocytic (ALL, CLL) lymphomas

Nausea, vomiting, myelosuppression

53
Q

Indications for Cladiribine?

A

Hairy cell leukemia

CLL

54
Q

Toxicities for Cladiribine?

A

Nausea
Vomiting
Infections myelosuppression

55
Q

Indications for Clofarabine?

A

Pediatric ALL after 2 previous failed treatments

Pediatric and adult AML

56
Q

Toxicities with Clofarabine?

A

Bone marrow suppression, hypotension, capillary leak syndrome

57
Q

Indications for Nelarabine?

A

T-cell leukemia and T-cell malignancies

58
Q

Toxicities for Nelarabine?

A

Myelosuppression
Abnormal liver function tests
Seizures, delirium, peripheral neuropathy

Cology 2 Exam 4 (16 decks)

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