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Prof J.E.Brown Password: CCL.

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Presentation on theme: "Prof J.E.Brown Password: CCL."— Presentation transcript:

1 Prof J.E.Brown Password: CCL

2 Outline of Lectures  Anthracyclines, Dactinomycin; Bleomycin, Mitomycin; Procarbazine and their mechanisms of action  Drugs inhibiting microtubule formation eg: vinblastine, vincristine; Microtubule enhancers eg: Paclitaxel  Nucleotide biosynthesis; Cytidine analogues, fluorinated pyrimidines, purine analogues  Hormone antagonists - Use of and mechanism of action of anti- oestrogens such as tamoxifen, anti-androgens and adrenal hormone synthesis inhibitors. 2

3 Lecture 1  Anthracyclines  Dactinomycin  Bleomycin  Mitomycin  Procarbazine  Mechanisms of action  Chemotherapy 3

4 Anthracyclines Includes some of the most clinically important chemotherapeutic agents:  Doxorubicin (Adriamycin)  Epirubicin  Daunorubicin  Idarubicin  These are some of the most effective and important drugs used in cancer chemotherapy today  Antibiotic derived from the bacterium Streptomyces peucetius  These drugs are termed “antitumour antibiotics” and were initially developed for their antibiotic properties  Doxorubicin is used in many chemotherapeutic regimes for a broad range of tumour types 4

5 Anthracycline Structure 5

6 Clinical Uses of Anthracyclines Anthracyclines are principally used against haematopoietic malignancies including:  acute leukaemias  Hodgkin’s and non-Hodgkin’s lymphomas  multiple myeloma But also solid tumours:  carcinomas of the breasts, lung, ovary stomach and thyroids  sarcomas of bone and soft tissues  Epirubicin is very widely used in many treatment regimens  All anthracyclines cause a dose- related cardiomyopathy 6

7 Mode of Action of Anthracyclines  The mode of action of doxorubicin and daunorubicin is via reversible binding to nucleolar DNA  this inhibits DNA replication leading to cell death.  NMR spectroscopic and X-ray crystallographic studies have shown that anthracyclines intercalate into the B-form of the DNA double stranded helix with guanine-cytosine d(CpG) site-specific interactions  The DNA base pairs above and below the drug 'buckle' in conformation resulting in a distorted DNA helix  This inhibits DNA from binding with DNA helicase, DNA topoisomerase II and polymerase families of enzymes  Prevents DNA replication for RNA synthesis, protein formation and thereby cell division. 7

8 DNA Intercalation 8

9 Dactinomycin  Dactinomycin (or actinomycin D) is a chromopeptide antineoplastic antibiotic isolated from Streptomyces parvulus  Dactinomycin intercalates between adjacent guanine-cytosine base pairs, blocking the transcription of DNA by RNA polymerase  At higher concentrations, it also inhibits DNA synthesis. Interstrand and DNA-protein cross-links may also occur.  It also causes single-strand DNA breaks, possibly via a free-radical intermediate or an interaction with topoisomerase II  It is used in the treatment of Ewing's sarcoma, Rhabdomyosarcoma and Wilm's tumour 9

10 Dactinomycin Structure 10  Dactinomycin consists of a phenoxazone ring system, to which two cyclic pentapeptides are attached (α and β rings)  The aromatic ring system is well apt to intercalate into DNA, preferably at GC steps

11 Bleomycin  Bleomycin A 2 Structure  Glycopeptide Antibiotic produced by the bacterium Streptomyces verticillus  Chemotherapeutics agents usually A 2 and B 2 forms  Used in the treatment of Hodgkin’s lymphoma, squamous cell carcinomas, and testicular cancer 11

12 Mechanism of Action of Bleomycin  Bleomycin acts by induction of DNA strand breaks.  Bleomycin may also inhibit incorporation of thymidine into DNA strands  DNA cleavage by bleomycin depends on oxygen and metal ions  Bleomycin probably chelates metal ions (primarily iron) producing a pseudoenzyme that reacts with oxygen to produce superoxide and hydroxide free radicals that cleave DNA  In addition, these complexes are also involved in lipid peroxidation and oxidation of other cellular molecules. 12

13 Mitomycin C 13 The mitomycins are a family of aziridine-containing natural products isolated from Streptomyces lavendulae and is an antitumour antibiotic chemotherapeutic agent It is given intravenously to treat upper gastro- intestinal (e.g. oesophageal carcinoma) and breast cancers, as well as by bladder instillation for superficial bladder tumours. It causes delayed bone marrow toxicity and administered at 6-weekly intervals. Prolonged use may result in permanent bone- marrow damage and it may also cause lung fibrosis and renal damage

14 Mechanism of Action of Mitomycin C  Mitomycin C is a potent DNA crosslinker with a single crosslink  This is accomplished by reductive activation, followed, by two N- alkylations  Both alkylations are sequence specific for a guanine nucleoside in the sequence 5'-CpG-3‘  This results in mispairing of bases, DNA strand breakage, and cross- linking of complementary strands which prevents DNA synthesis  DNA-dependent RNA polymerase is also inhibited decreasing transcription.  The drug may also lead to mutations in DNA. 14

15 Procarbazine  Procarbazine is a methylhydrazine alkylating agent used for the treatment of Hodgkin's lymphoma and certain brain cancers (such as glioblastomas).  It is metabolized and activated in the liver and this yields azo- procarbazine and hydrogen peroxide which results in the breaking of DNA strands 15

16 Mechanism of Action of Procarbazine  After metabolic activation, procarbazine appears to inhibit the trans-methylation of methionine into transfer RNA (t- RNA)  This prevents protein synthesis and consequently DNA and RNA synthesis  This agent may also undergo auto-oxidation, resulting in the formation of cytotoxic free radicals which damage DNA through an alkylation reaction 16

17 Conclusions  All anticancer drugs discussed in lecture interfere with DNA or RNA synthesis  Anticancer drugs are almost never used alone, but are used in combination  Drugs are highly toxic, cause myelosuppression, mucositis and alopoecia  Must use high dose, intermittent therapy  Anthracyclines and alkylating agents are most widely used  Anthracyclines cause dose- limiting cardiomyopathy 17

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