Anticancer: Target DNA

Question 1

Cisplatin

Answer 1

Platinum compound - covalently binds DNA
Cross links N7 atom of guanine and adenine - particularly intrastrand neighbouring guanines
Causes bend towards major groove -| DNA polymerase -| replication

Question 2

Doxorubicin

Answer 2

Anthracycline
Planar rings which intercalate between bases -> local unwinding -> changes in major and minor grooves -| DNA + RNA pol + t factors
Toxicity: produces ROS in conversion to and from semiquinone which cause heart damage

Question 3

Mitoxanthrone

Answer 3

Anthracycline
Planar rings which intercalate between bases -> local unwinding -> changes in major and minor grooves -| DNA + RNA pol + t factors
Like doxorubicin except does not produce free radicals -> lower toxicity

Question 4

Cyclophosphamide

Answer 4

Nitrogen mustard- covalently binds DNA
Orally administered, activated by p450s in liver to phosphoramide mustard
Contains two chloroethyl groups -> immonium ion intermediates -> attack guanine bases and cross link them
Cross links may occur on one strand or between strands
This activates repair mechanisms leading to endonuclease attack and potentially activation of apoptosis by p53
Immonium ions may also attack other nucleophilic groups on DNA, RNA, proteins leading to generalised toxicity
May also lead to monoalkylated guanine -> base pairs T -> AT transition

Question 5

Methotrexate

Answer 5

Folic acid antagonist
Inhibits DHFR (see diagram)
Prevents DNA synthesis
Coadministered with leucovorin to reduce side effects

Question 6

Leucovorin

Answer 6

Reduces toxicity effects of methotrexate to normal cells by supplying alternative methyltetrahydroxyfolate source via different reaction pathway

Question 7

Etoposide

Answer 7

Inhibits topoisomerase II

Question 8

Topotecan

Answer 8

Inhibits topoisomerase I

Question 9

Vinca alkaloids

Answer 9

Vinblastin, vincristine, taxol
Interfere with micro tubule formation by disrupting equlibrium between free tubulin dimers and microtubules
Taxol increases microtubule polymerisation -> abnormal bundles
The others inhibit formation thereby inhibiting mitosis