Lecture 41 + 42

Question 1

All alkylating agents and Platinum coordinators act via ____-_____ DNA.

Answer 1

Cross-Linking DNA

Question 2

_____ dehydrogenase is expressed in low levels in cancer cells, so the toxic phosphoramide mustard produced by nitrogen mustards is not detoxified efficiently, while in normal cells it would be.

Answer 2

Aldehyde Dehydrogenase

Question 3

Methotrexate is a ____ acid analogue (antimetabolite) and inhibits dihydrofolate reductase, which is an enzyme necessary to synthesize ______ monophosphate. The buildup of precursors in this pathway inhibit ______ synthase. Being that it blocks the production of nucleotides, which phase of the cell cycle might this drug work in?

Which organs does this drug become toxic for at high and low doses respectively?

Answer 3

Folic Acid

Thymidine monophosphate

Thymidylate synthase

S-phase

High –> kidney

Low –> liver

Question 4

5-flurouracil is a pyrimidine analogue that can disrupt DNA synth but can also inhibit _____ synthase (remember methotrexate results in this also)

Answer 4

Thymidylate synthase

Question 5

Cytarabine is a nucleoside cytosine analogue that has a trans OH in the C__ position, so it inhibits pairing with Gunaine. This is used to treat which leukemia?

Answer 5

C2

AML

Question 6

6-Mecaptopurine is metabolized into T(IMP), which inhibits the production of ____ and ____, which normally uses Inosinic acid. Also, buildup of T(IMP) induces a negative feedback mechanism which inhibits _________, the enzyme that produces Phosphoribosylamine from Glutamine and PRPP.

Answer 6

AMP

GMP

Amidotransferase

Question 7

Paclitaxel, Vinblastine, and Vincristine are anti_____ drugs that act during mitosis. While Vinblastine and Vincristine bind tubulin dimers and prevent _______, Paclitaxel binds and stabilizes _______, preventing their breakdown. Keep in mind cancer cells upregulate expression of the _____-1 gene, which is a Ca++ dependent pump that pumps out the chemo drugs, which is particularly effective against this class of drugs.

Answer 7

AntiTubulin

Polymerization

Microtubules

mdr-1 (Multidrug resistance)

Question 8

________ is an Actinomycin (antibiotic) that binds dsDNA and thus blocks transcription. Because it binds the double helix, is it cell-cycle dependent or independent? Keep in mind it does NOT cross the ____.

Answer 8

Dactinomycin

Independent

BBB

Question 9

Anthracyclins and Anthracenediones (all the “-rubicins”) can act in three different ways.

1. They can _____ with DNA and disrupt it.
2. They form a tripartite complex with DNA and ______ II (preventing resealing of DNA after it’s cleaved to relieve trosional strain).
3. The hydroquinone and quinone moieties in these drugs allows for electron transfer and generation of ______ radicals (facilitated by interaction with iron) that disrupt DNA. This also makes these drugs highly toxic to which organ?

Answer 9

1. Intercalate
2. Topoisomerase II
3. Superoxide radicals

Question 10

Epipodophyllotoxins (the “-posides”) are active in the ____ and G__ phases of the cell cycle as they form a ternary complex with DNA and _______II, preventing the DNA from resealing –> accumulation of breaks leads to cell death.

Answer 10

S and G2

Topoisomerase II

Question 11

Bleomycins are typically administered as combinations and act by complexing with _____ (which metal ion?) and DNA, inducing oxidative damage in the ____2 phase of the cell cycle.

Answer 11

Fe++

G2