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LHT1 > Cancer chemotherapy and Anti-neoplastics 2 > Flashcards

Cancer chemotherapy and Anti-neoplastics 2 Flashcards

1
Q

Folate anti-metabolite drugs

A
  • Methotrexate

- Pemetrexed

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2
Q

Purine anti-metabolite drugs

A
  • 6-mercaptopurine
  • 6-thioguanine
  • fludarabine
  • cladribine
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3
Q

methotrexate- distinctions

A
  • inhibits DHFR- blocks syn of thymidine, methionine, and serine
  • MTX metabolite inhibits GAR and AICAR transformylase- blocks syn of purines
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4
Q

pemetrexed- distinctions

A
  • inhibitor of thymidylate synthase and GAR transformylase
  • less potent inhibition of DHFR compared to MTX
  • can circumvent MTX resistance
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5
Q

methotrexate- used for?

A
  • choriocarcinomas (monotherapy)!!!

- pediatric leukemias, primary CNS lymphoma, non-Hodgin lymphoma

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6
Q

Pemetrexed- used for?

A

-malignant pleural mesothelioma! (used with cisplatin)

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7
Q

high dose methotrexate- used for?

A
  • CNS prophylaxis in pts with leukemia and lymphoma

- followed by 2-3 day “rescue” with leucovorin!!

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8
Q

intermediate dose methotrexate- used for?

A

-choriocarcinoma

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9
Q

low dose methotrexate- used for?

A

intrathecal for CNS prophylaxis

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10
Q

methotrexate- dose-limiting toxicity

A
  • bone marrow suppression!
  • high dose- risks renal crystalluria of MTX and renal failure
  • high dose- requires leucovorin rescue!
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11
Q

pemetrexed- dose-limiting toxicity

A
  • bone marrow suppression

- caution in pts with moderate renal insufficiency (co-treatment with NSAIDS!)

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12
Q

methotrexate- moa

A
  • enters cells via RFC (energy dep transport)
  • competitive inhibition of DHFR- main moa!!- causes accum of DHF
  • accum in cells as MTX(glu)n- inhibits DHFR and AICAR and GAR transformylase
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13
Q

low dose methotrexate- clearance

A

-80% renal excretion

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14
Q

high dose methotrexate- clearance

A
  • hepatic metabolism
  • 7-hydroxy-MTX (inactive, less soluble)
  • renal elimination- crystalluria tubular obstruction!!!!
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15
Q

Pemetrexed- moa

A
  • competitive inhibition of TS and GAR transformylase- main moa!!!
  • accum in cells as a polyglutamate- inhibits TS and GAR transformylase
  • has a negligible effect of DHFR, compared to MTX’s effect!!!!
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16
Q

Pemetrexed- clinical significance

A

-survival benefit with cisplatin in malignant pleural mesothelioma!!!!

17
Q

6-Mercaptopurine- distinctions, therapeutic uses, dose limiting toxicity

A
  • inhibits purine ring biosyn and nucleotide interconversion- disrupts DNA and RNA integrity
  • maintenance of remission in ALL (acute lymphocytic leukemia)!!
  • myelosuppression!!; dose adjustment with allopurinol or febuxostat (xanthine oxidase inhibitor)
18
Q

6-Thioguanine- distinctions, therapeutic uses, dose limiting toxicity

A
  • inhibits purine ring biosyn and nucleotide interconversion- disrupts DNA and RNA integrity
  • acute-NON-lymphocytic leukemia
  • myelosuppression
19
Q

Fludarabine- distinctions, therapeutic uses, dose limiting toxicity

A
  • tumor cell kinases convert to nucleotide triphosphates- inserted into DNA, RNA, and disrupt DNA/RNA syn
  • CLL (chronic lymphocytic leukemia!!
  • myelosuppression
20
Q

Cladribine- distinctions, therapeutic uses, dose limiting toxicity

A
  • tumor cell kinases convert it to nucleotide analogs; inhibits DNA syn; inhibitor of ribonucleotide reductase
  • hairy cell leukemia!!!
  • myelosuppression
21
Q

6-Mercaptopurine- hepatic inactivation

A
  • hepatic inactivation via TPMT and XO (xanthine oxidase)
  • TPMT–> Methyl-6-MP (inactive)
  • XO–> 6-Thiouric acid (inactive)
22
Q

6-Mercaptopurine- bioactivation

A
  • HPRT-> TIMP
  • -TPMT–> active
  • -IMPDH–> active
23
Q

clinical significance of HPRT bioactivation

A

-converts 6-MP to active metabolites- inhibits purine biosyn!!

24
Q

Toxicological significance of hepatic metabolism

A
  • low bioavailability- XO metabolizes 80% of 6-MP!

- excess exposure (drug interactions)- inhibition of xanthine oxidase by gout medications

25
Q

6-Mercaptopurine- drug interactions

A

-inhibition of xanthine oxidase by gout medications!- allopurinol, febuxostat!!

26
Q

Thioguanine- moa

A

-bypasses the XO inactivation step! (no drug interactions with XO inhibitors)

27
Q

Fludarabine and Cladribine- moa

A

(chemical analogs of adenosine)- 2’ position of sugar
-inside tumor cells, kinase enzymes convert them to nucleotide tri-phosphates- these active metabolites inhibit DNA polymerase and can incorporate into DNA and RNA

28
Q

Pyrimidine, Folate, Purine Antimetabolites- what part of cell cycle are the tumor cells vulnerable?

A

-S cycle!!

29
Q

-S cycle!!

A

-G1 and G2- Gap phases- cell Grows and prepares to divide
-S- Synthesis phase (cell duplicates DNA)
-M- Mitotic phase (divides into 2 daughter cells)
-Go- resting state- cells not actively dividing
(G1, S, G2, M, Go)

LHT1 (6 decks)

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