Antineoplastic agents I Flashcards
are tumor cells with shorter doubling time easier or more difficult to treat?
easier
cell kill hypothesis
chemotherapy drugs kill a constant proportion of cells, not a constant number - first order kinetics
defintion: epithelial-mesenchymal transition
a process by which cell lose adhesive properties and become motile (leads to metastasis and drug resistance)
how do the cytotoxic cancer drugs work?
- perturbing normal DNA replication
- perturbing mitosis
- starving cells of amino acids
how do the targeted cancer drugs work?
- perturbing hormone and growth factor signaling
- inhibiting blood supply to tumor
- targeting activating proteins responsible for tumor growth
what is the classification of adenine and guanine?
purine bases
what is the classification of thymine, cytosine, and uracil?
pyrimidine bases
what is the classification of adenosine and guanosine?
purine nucleosides
what is the classification of thymidine, cytidine, and uridine?
pyrimidine nucleosides
what is the classification of AMP and GMP?
purine nucleotides
what is the classification of TMP, CMP, and UMP?
pyrimidine nucleotides
what is the goal of the antimetabolite cancer drugs?
inhibiting de novo nucleotide biosynthesis
what is required for the conversion of purine precursors to inosine monophosphate (IMP)?
folate
what is the general mechanism of action for methotrexate?
inhibits dihydrofolate reducatse - reduces precursors for RNA and DNA synthesis
what are the main therapeutic uses for methotrexate?
- ALL in children
2. osteosarcomas (high doses)
following methotrexate with which drug reduces toxicity?
leucovorin
what are the mechanisms of resistance against methotrexate?
- impaired transport
- DHFR with decreased affinity to methotrexate
- elevated HDFR expression
what are the toxicities of methotrexate?
- interstitial pneumonitis
- nephrotoxic
- bone marrow suppression
what is the general mechanism of action for 5-fluorocuracil?
- incorporated into DNA and RNA - inhibits synthesis and function
- inhibits thymidylate synthetase - reduces precursors
what are the adverse effects of 5-fluorouridine?
oral and GI ulcers
what does capecitabine do?
prodrug of 5-FU that has improved oral bioavailability allowing it to be given orally
cytarabine is used for what type of cancer?
AML
what is the general mechanism of action of cytarabine?
- incorporates into DNA and RNA
2. inhibits DNA polymerase
cytarabine is only active in which phase of the cell cycle?
S phase
which enzyme is important for activation of Ara-C (cytarabine)?
deoxycytidine kinase
what is the role of cytidine deaminase?
inactivates Ara-C (cytarabine)
what are the toxicities of cytarabine?
- cerebellar syndrome
2. myelosuppression
what are the features of cerebellar syndrome?
- dysarthria
- nystagmus
- ataxia
why does cytarabine cause cerebellar syndrome?
gets to high levels in the CNS because dytidine deaminase levels are low in the CNS
what is the primary resistance mechanism of cytarabine?
loss of deoxycytidine kinase
upregulation of which enzyme leads to inactivation of Ara-C and resistance against cytarabine?
cytidine deaminase
what is the mechanism of action of gemcitabine?
- incorporates into DNA, inhibits synthesis
2. inhibits ribonucleotide reductase - reduces precursors
what is the the mechanism of resistance for gemcitabine?
reduced activity of deoxycytidine kinase
