Antitumour Antibiotics PHL 417

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

1. Anthracyclines Doxorubicin Daunorubicin Epirubicin metozantrone

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

One electron Reduction of DOX

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

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

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

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

2- Chronic Cardiotoxicity * Cumulative * Dose-dependent * Irreversible * Upper safe limit (400-500 mg/m2) * Affects 30-40 % of the patients who receive a cumulative dose more than 400 mg/m2. Tumour growth CHF

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.

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

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

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

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

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