1. Antitumour Antibiotics PHL 417

2. Antibiotics Anthracyclines- Doxorubicin & Daunorubicin Dactinomycin
Bleomycin
Most of the antibiotics work by binding to DNA thru 1) intercalation btw base pairs and (-) of new RNA or DNA 2) cause DNA strand scission 3) and interference with cell replication
All of the clinically useful anticancer antibiotics are products of various strains of the soil fungus Streptomyces

3. 1. Anthracyclines
Doxorubicin
Daunorubicin
Epirubicin
metozantrone

4. Anthracyclines (cont.) Mechanism of Action
They intercalate in between base pairs of DNA and thus inhibiting the supercoiling of the double helix and so preventing DNA and RNA synthesis. They insert nonspecifcally between adjacent base pairs and bind to the sugar-phosphate backbone of DNA
The main cytotoxic action appears to be induction of single and double strand DNA breaks by either generation of free radicals or their effect on DNA Top II.
Anthracyclines react with cyt. P450 reductase in the presence of NADPH to form semiquinone radicals intermediates. This in turn reduce molecular O2, producing superoxide anion & hydrogen peroxides which mediate DNA strand breaks
The generation of free radicals lead to cardiac toxicity thru oxygen radical mediated damage to membranes

6. One electron Reduction of DOX

8. Anthracyclines (cont.) Mechanism of Resistance
Pleiotropic drug resistance due to P-glycoprotein production.
Increased GSH peroxidase activity.
Decreased topoisomerase II activity.

9. Anthracyclines (cont.) Therapeutic Uses
Doxorubicin- carcinomas of the breast, endometrium, ovary, testicle, thyroid, and lung
Daunorubicin- acute leukemia

10. Anthracyclines (cont.) Toxicity
Bone marrow depression
Total alopecia
Cardiac toxicity: Doxorubicin causes cumulative dose-related cardiac damage leading to dysrrhythmias and heart failure. This action may be due to free radical generation and interaction of Doxorubicin with iron.
Cardiac toxicity involves excessive intracellular production of free radicals with the myocardium, Tx with antioxidants like vitamin E

11. Doxorubicin-Induced Cardiotoxicity
1- Acute Cardiotoxicity:
Arrhythmia
Pericarditis-Myocarditis Syndrome.
Congestive Heart Failure.

12. 2- Chronic Cardiotoxicity
* Cumulative
* Dose-dependent
* Irreversible
* Upper safe limit
( mg/m2)
* Affects % of the patients who receive
a cumulative dose more than 400 mg/m2.
Tumour
growth
CHF

13. Therapeutic Strategies for DOX-Induced Cardiotoxicity:
1. Dexrazoxane (cardioxan ® (Iron Chelator) must given as 1gm/m2 IV bolus, 1 hour before doxorubicin.
2. Administration of DOX as infusion (60 mg/m2/96 hours).
3. Reducing the total cumulative dose to <400 mg/m2.
4. Using liposome-encapsulated Doxorubicin.
5. Antioxidants and vitamins.
6. ACE Inhibitors.
7. Beta-blockers.

14. 2. Dactinomycin Mechanism of Action
Known as actimomycin D
It is one of a series of antibiotics obtained from Streptomyces microorganism
It was the first antibiotic to find therapeutic application in cancer chemotherapy
The drug intercalates into the minor groove of the double helix between guanine-cytosine base pairs of DNA
The complex interfere primarily with DNA-dependent RNA polymerase, although at high doses it also hinders DNA synthesis.
It may induce DNA strand breaks by inhibiting topoisomerase II or by generation of free radicals
3 D’s intercalate between base pairs
Ribosomal RNA formation being most sensitive to drug action
DNA replication is less effected, while protein is blocked
The degree of cytotoxic effect is determined by the cells ability to accumulate and retain the antibiotic
Drug is mainly excreted in the bile

15. Toxicity Therapeutic Uses
With MTX in treatment of gastrointestinal carcinoma
Toxicity
Bone marrow depression
Oral ulcers
Dermatological manifestation including alopecia, erythrema, inflammation and skin pigmentation

16. 3. Bleomycin Mechanism of Action
A DNA-bleomycin-Fe2+ complex appears to undergo oxidation to bleomycin-Fe3+. The liberated electrons react with oxygen to form superoxide or hydroxyl radicals, which in turn attack the phosphodiester bond of DNA, resulting in strand breaks
It is cell cycle specific and causes cells to accumulate in G2 phase
A mixture of 11 different glycoproteins are used in therapy, the major components being A2 and B2

17. Bleomycin (cont.) Mechanism of resistance
Bleomycin is degraded by hydrolase enzyme. Increases the hydrolase level leads to development of resistance
Increase efflux of drug
Enhancement of DNA repairing capacity
Inflammation is the connective tissue in the lungs

18. Bleomycin (cont.) Therapeutic Uses
Testicular cancer
Squamous cell carcinomas of the head and neck, cervix, skin and rectum
Lymphomas
Toxicity
Lethal anaphylactoid reactions
Pulmonary fibrosis