1. Antitumour Antibiotics PHL 425 Dr. Mohamed M. Sayed-Ahmed

2. Antitumour Antibiotics Anthracyclines Doxorubicin Daunorubicin Epirubicin Idarubicin Mitoxantrone Bleomycin Mitomycin-C Dactinomycin Plicamycin

3. Anthracyclines Doxorubicin Daunorubicin

4.  Chemical structure:  Origin: produced by the fungus streptomyces peucetius  Class: Anthracycline antibiotic  Trade names: ® Adriamycin ® Doxil ® Rubex

5.  Advantages of Doxorubicin 1. It has a broad spectrum antitumor activity. 2. Lack of antagonism with any cytotoxic drug makes DOX good candidate in design of combination chemotherapy protocols 3. Flexibility of dosing and scheduling. 6o mg/m2 every 3 weeks (higher cardiotoxicity) 20 mg/m2 every week (moderate cardiotoxicity) 60 mg/m2/96 hours infusion (lower cardiotoxicity) 4- It destroys basement membrane, so it is effective in treatment of metastatic tumours.

6. Indications of Doxorubicin  FDA labeled indications: AIDS-related Kaposi's sarcoma. Multiple myeloma ( In combination with bortezomib) Ovarian carcinoma. Non-Hodgkin's lymphoma, Advanced Non-small cell lung cancer, Advanced  Acute and chronic lymphoid leukemia Carcinoma of prostate, Advanced Carcinoma of stomach, Advanced

7. Indications of Doxorubicin  Non-FDA labeled indications: Breast cancer. Multiple myeloma (In combination with vincristine and dexamethasone) Carcinoma of cervix Endometrial carcinoma Osteosarcoma of bone Soft tissue sarcoma

8.  Mechanism of Antitumour Activity DOX induces both DNA-single and double strand breaks which is believed to be mediated either by 4 mechanisms including: 1.DNA intercalation that inhibits macromolecular biosynthesis. 2- inhibition of DNA-Topoisomerase I and DNA-Topoisomerase II Thus preventing DNA replication 3. Generation of free radicals through Enzymatic one electron reduction of doxorubicin by a variety of oxidases, reductases and dehydrogenases and complex with iron generates highly reactive free radicals species (DOX-iron complex induces cardiotoxicity). 4. DNA Alkylation through Two electron reduction and generation of quinone methid after losing its sugar part.

9. One electron Reduction of DOX

10. Administration As a single agent most common dose is 60 to 75 mg/m2 as a single intravenous injection administered at 21 day intervals. When used in combination with other chemotherapy drugs, dose is 40 to 60 mg/m2 given as a single intravenous injection every 21 to 28 days. Recommended maximum cumulative doses No risk factors: 550 mg/m2 Risk factors: 450 mg/m2 Concurrent radiation: 250 mg/m2

11. Toxicity of Doxorubicin  Cardiotoxicity.  Secondary Leukemia  Acute infusion-related reactions.  Hematologic Toxicity  Alopecia occurs in the majority of patients.  Extravasation injury produce extensive local necrosis.  Gastrointestinal disturbances: Nausea, vomiting, stomatitis and oesophagitis may progress to ulceration.

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

13. 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. CHF Tumour growth

14. Mechanisms of DOX-Induced Cardiotoxicity 1- Increase levels of circulatiing catecholamines 2- Generation of free radicals (Why the heart) 3- Interaction of DOX with Iron ( Role of Dexrazoxane) 4- Cardiac calcium overload 5- Inhibition of Long-Chain Fatty Acid Oxidation in the heart (Role of L-carnitine)

15. Risk factors in DOX Cardiotoxicity 1. Cumulative dose more than 450 mg/m2. 2. Age greater than 70 years. 3. Pre-existing cardiac disease. 4. Concomitant treatment with cyclophosphamide and other cardiotoxic drugs. 5.Thoracic Irradiation more than 2000 rads 6. Chronic hypertension.. 7. Hepatobillary dysfunction Bilirubin less than 1.5 ug/dl (full DOX dose) Bilirubin 1.5-3 ug/dl (reduce DOX dose by 50 %) Bilirubin 3-5 ug/dl (reduce DOX dose by 75 %) Bilirubin more than 5 ug/dl (omit DOX)

16. Diagnosis of DOX cardiotoxicity Cardiac Markers: CK-MB, LDH, Troponine Radionuclide angiography (MUGA) Echocardiography (ECHO). An ECG changes such as dysrhythmias, a reduction of the QRS voltage. Endomyocardial biopsy

17. Therapeutic Strategies for DOX- Induced Cardiotoxicity : 1. Dexrazoxane (cardioxan ® 1gm/m2 IV bolus, 1 hour before doxorubicin. 2. L-carnitine 1 gm 3 times daily orally for 3 days before and 3 days after DOX plus 1 gm IV during DOX infusion. 3. Administration of DOX as infusion (60 mg/m2/96 hours). 4. Reducing the total cumulative dose to <400 mg/m2. 5. Using liposome-encapsulated Doxorubicin. 6. Antioxidants and vitamins. 7. ACE Inhibitors. 8. Beta-blockers.

18. Secondary Leukemia The occurrence of secondary Leukemia has been reported most commonly in patients treated with chemotherapy regimens containing doxorubicin and DNA-damaging antineoplastic agents, in combination with radiotherapy, when patients have been heavily pretreated with cytotoxic drugs.

19. Extravasation Injury by Doxorubicin Redness, swelling blisters Tissue necrosis surgery to remove tissue permanent damage

20.  Extravasation management 1. Apply ice Cooling of site injection will inhibits vesicant's cytotoxicity. (heat or sodium bicarbonate can be harmful ). 2. topical dimethylsulfoxide or local hydrocortisone (100 mg/2 mL) 3. topical DMSO (1.5 mL of a 50% solution every 6 hours for 2 weeks)

21. Resistance to Doxoruinbic 1.High level of glutathione (GSH) lead to resistant to doxorubicin. 2. Altered topoisomerases. 3. Multidrug resistance (MDR). Reversal of Doxoruinbic Resistance by: 1. GSH depletion by using buthionine sulfoxamine (BSO). 2. Transfer of fully active topoisomerase II gene into resistant cells 3. Using MDR blockers such as Verapamil

22. Dactinomycin (Actinomycin D) Dactinomycin was the first antibiotic used in cancer chemotherapy It affects cells in all phases of the cell- cycle i.e. CCNS Dactinomycin is given intravenously, it remains unchanged and is concentrated in the liver and excreted in bile It does not cross the blood-brain barrier

23. Minor Groove Major Groove

24. M echanism of action of Dactinomycin Minor Groove D D  By an effect on topoisomerase II that unwinds the DNA helix for replication  It intercalates, in the minor groove of DNA, between adjacent guanine- cytosine pairs thus preventing transcription

25. M echanism of action of Dactinomycin Minor Groove D D  By an effect on topoisomerase II that unwinds the DNA helix for replication  It intercalates, in the minor groove of DNA, between adjacent guanine- cytosine pairs thus preventing transcription

26. Adverse Effects Bone marrow depression is the major dose-limiting toxicity (leucopenia and thrombocytopenia) Nausea, vomiting, diarrhea, oral ulcers alopecia and skin eruptions may also be noted Dactinomycin sensitizes to radiation; inflammation at sites of prior radiation therapy may occur

27. Bleomycin: a metal-chelating antibiotic B B DNA- bleomycin-Fe 2 + complex intercalate between base pair Fe Generate free radicals (superoxide, hydroxyl radicals) DNA strands breaks DNA- bleomycin-Fe 3+

28. Bleomycin-Mechanism of action Acts through binding to DNA, which results in single and double strand breaks following free radical formation and inhibition of DNA synthesis The DNA fragmentation is due to oxidation of a DNA-bleomycin-Fe(II) complex and leads to chromosomal aberrations Cell Cycle Specific drug that causes accumulation of cells in G2

29. Bleomycin is most effective in the G2 phase of the cell cycle and mitosis, but it is also active against non- dividing cells (i.e. cells in the G0 phase; DNA+ bleomycin +ferrous iron …….> undergoe oxidation to ferric ion the liberated electrons react with oxygen to produce superoxide hydroxyl radicals….> strands breaks in DNA

30. Clinical uses of Bleomycin Bleomycin is most effective in the G2 phase of the cell cycle and mitosis, but it is also active against non-dividing cells (i.e. cells in the G0 phase) CCNS It is used to treat germline cancer  Testicular carcinoma  Hodgkin ’ s lymphoma

31. Adverse effects of Bleomycin Skin toxicity: Alopecia, blisters and hyperkeratosis Hypersensitivity reactions; fever, chills,… It is not a myelosuppressant

32. Adverse effects of Bleomycin Hydrolase ( bleomycin inactivating enzyme) is deficient in the lung and skin