Lecture 3 Non-covalent bonding drugs

Question 1

noncovalent binding drugs

Answer 1

anthracyclines**

other abx

Question 2

Anthracyclines

Answer 2

• produced by streptomyces peucetius bacteria
• minor structural modifications = wide change in activity
• wide range of compounds have been screened
• 7 are in clinical use

Question 3

Daunorubicin/daunomycin

Answer 3

isolated from Streptomyces
use limited to induction tx of acute leukemia
- use at high dose for induction - to destroy malignant cells and induce healthy cell growth

Question 4

Doxorubicin/adriamycin

Answer 4

isolated from mutated strain of same fungus (streptomyces). More effective in tx of solid tumors. Most widely used

Question 5

semisynthetic anthracyclines

Answer 5

Epirubicin - stereoisomer of doxorubicin. More lipophilic

Idarubicin - primarily for acute leukemia - replaced daunorubicin

Question 6

MOA of rubicins

Answer 6

1. DNA intercalation
2. ROS formation
3. Topoisomerase II inhibition
   inhibits DNA and RNA synthesis
   Cell cycle non-specific

Question 7

DNA intercalation

Answer 7

planar drugs intercalate between the DNA bases = DNA breakage
Blocks DNA synthesis and transcription

Question 8

Reactive Oxygen Species

Answer 8

not a single species
Oxygen free radicals, hydrogen peroxide, hydroxyl radicals
bind to DNA/RNA protein and damage, as well as damage to proteins and lipids in both tumor and normal cells

Question 9

ROS SE

Answer 9

cardiac toxicity
free radicals (lipid peroxidation) may damage heart muscle 
hard to predict
oncologists monitor carefully.
may survive chemo, but die from SE

Question 10

Topoisomerase II inhibition

Answer 10

Breaks and re-ligates double-strand DNA for transcription and replication
break strand = inhibit synthesis and replication
usually cell-cycle S-phase sensitive

Question 11

Resistance to anthracyclines

Answer 11

enter cell via passive diffusion = high intracellular concentration

1. substrate for Pgp efflux pump
2. drug resistance results from mutations in topoisomerase II

Question 12

Daunorubicin toxicity

Answer 12

cardiotoxicity, alopecia, and bone marrow depression

Question 13

Doxorubicin

Answer 13

cardiotoxicity, alopecia, bone marrow depression, and stomatitis

Question 14

Idarubicin

Answer 14

cardiotoxicity, mucositis, and bone marrow depression

Question 15

Bleomycin

Answer 15

isolated from steptococcus verticillus
small peptide with a DNA-binding region (intercalation) and an iron-binding region (free-radical)
similar to anthrocyclines

Question 16

Bleomycin MOA

Answer 16

1. DNA intercalation = DNA breakage

2. Hydroxyl free radicals formation = DNA breakage (complex with divalent cation, such as iron)

Question 17

Bleomycin toxicity

Answer 17

1. minor myelosuppression
2. pulmonary fibrosis = only drug that does this
3. toxicities do not overlap with other drugs
4. important in combo tx