Lecture 5 Chromatin Inhibitors

Question 1

chromatin inhibitors derived from

Answer 1

plants

Question 2

Topoisomerases function

Answer 2

enzymes that regulate DNA supercoiling

Two types: type 1 and type 2

Question 3

How does type 1 topo work

Answer 3

cuts into DNA and makes a nick, DNA relaxes

Question 4

how does type 2 topo workd

Answer 4

makes 2 cuts at same location, whole genome can be relaxed

Question 5

Topoisomerase I

Answer 5

changes the degree of supercoiling by causing:

1. single strand breaks
2. re-ligation (reseals the cut)

Question 6

Topoisomerase II

Answer 6

causes double strand breaks and then re-ligation

Question 7

Topoisomerase I inhibitors

Answer 7

camptothecin derivatives:
Topotecan/(hycamtin): advanced ovarian and small cell lung cancer
Irinotecan (CPT-11)/Camptosar: metastatic colon cancer

Question 8

MOA of camptothecin

Answer 8

bind Topo I and stabilize the complex

inhibitors allow uncoiling of DNA, but prevent subsequent re-ligation -> apoptosis

Question 9

Irinotecan

Answer 9

activated by liver carboxylesterases to SN-38
colon and rectal cancer
Cell cycle S phase specific

Question 10

Toxicity topotecan and Irinotecan

Answer 10

Topotecan (renal): acute: N/V; delayed: bone marrow depression
Irinotecan (bile): acute: N/V/D; delayed: severe diarrhea and bone marrow suppression

Question 11

Topoisomerase II inhibitors

Answer 11

Podophyllotoxin derivaties (etoposide and teniposide)
Mitoxantrone
Anthracyclines

Question 12

Podophyllotoxin derivatives

Answer 12

block religation reaction of topoisomerase II by a mechanism independent of DNA binding, leading ot the accumulation of protein linked single and double strand DNA breaks (cleavale complexes). Cells in the S and G2 phases of the cell cycle show the greatest sensitivity to these agents

Question 13

MOA of Topo II inhibitors

Answer 13

Normal topoisomerase II functioning:
1. Topoisomerase II-DNA complex.
2. Double-strand cleavage (transient)
3. Re-ligation.
In the presence of drug:
(4) Topoisomerase II-DNA complex is stabilized.
(5) Irreversible double strand breakage.

Question 14

Mitoxantrone (novantrone)

Answer 14

• Structurally similar to doxorubicin.
• Cell-cycle phase nonspecific, but most active in the late S phase.
• Produce less quinone type free radicals and cause less cardiac toxicity than doxorubicin (important!)
• For advanced hormone-refractory prostate ca and non-Hodgkin’s lymphoma.

Question 15

MOA of mitoxantrone

Answer 15

Topoisomerase II inhibition.

Nonintercalative DNA interactions.

DNA intercalation

Question 16

Nonintercalative DNA interactions

Answer 16

Mitoxantrone electrostatically interacts with DNA phosphate groups.

Electrostatic interaction -> DNA strand breaks

Question 17

DNA intercalation

Answer 17

• DNA intercalation = breakage

- Nonintercalative and intercalative effects -> reduced DNA and RNA synthesis.

Question 18

TOPO II inhibitors Toxicity

Answer 18

Etoposide: alopecia and bone marrow depression
Mitoxantrone: Bone marrow depression, occasional cardiac toxicity, mild alopecia