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					Anti cancer Drugs
         By


 Dr. Mobasher Ahmad
     Ph.D (Wales)
   Cancer chemotherapy: general
            principles
• The term ‘cancer’ refers to a malignant neoplasm (new
  growth).
• Cancer cells can manifest :
    Un controlled proliferation (no differentiation)
    invasiveness
    the ability to metastasise
. Most anticancer drugs are antiproliferative and will also
  affect rapidly dividing normal cells, and are thus likely to
  depress bone marrow, to impair healing, to depress growth,
  to cause sterility and hair loss, and to be teratogenic. Most
  cause nausea and vomiting.
           Drugs used in cancer
              chemotherapy
• Cytotoxic drugs:
• Alkylating agents: These act by forming covalent bonds
  with DNA and thus impeding DNA replication.
• Antimetabolites: These block or subvert one or more of
  the metabolic pathways involved in DNA synthesis.
• Cytotoxic antibiotics: These are substances of microbial
  origin which prevent eukaryotic cell division.
• Vinca alkaloids: These are substances of plant origin that
  specifically affect microtubule function and hence the
  formation of the mitotic spindle.
                      Contd
• Hormones:
                 Most important are steroids, namely
 glucocorticoids, oestrogens and androgens.
Sites of action of cytotoxic agents
     that act on dividing cells
               • Purine and Pyrimidine synthesis
•   6- Mercaptopurine, Thioguanine
    Inhibit purine sysnthesis, inhibit
     nucleotide interconversion.
Methotrexate: inhibition of dihydrofolate
Reductase leads to an inhibition of
purine ring and dTMP biosysthesis




                          • Ribonucleotides
                                Contd
         •                                  Ribonucleotides
• Methotrexate
• 5-Fluorouracil
(inhibit dTMP(2’deoxythymidylate)synthesis)
. Cytarabine
Terminates DNA chain elongation.
Incorporated into DNA and RNA
resulting in altered function of nucleic acids.
                                    Deoxy-ribonucleotides
                        Contd
                  Deoxy-ribonucleotides
. Cytarabine




                          DNA
Bleomycin, Doxorubicin,
Daunorubicin
Scission of DNA by an oxidative process.
                        Contd
                                                   DNA
• Dactinomycin,Doxorubicin, Daunorubicin
• Intercalate with DNA, disrupting DNA function.

• Alkylating agents Nitrosoureas Cisplatin
• Alter structure and function of DNA by
  cross-linking and or fragmenting of DNA strands.


                                                     RNA
Contd

  RNA




 Proteins
    Anticancer drugs: alkylating
   agents and related compounds
• Alkylating agents have alkyl groups which can form
  covalent bonds with cell substituents;a carbonium ion is
  the reactive intermediate.
• Most have two alkylating groups and can cross link two
  nucleophilic sites such as the N7 of guanine in DNA;
  cross-linking can cause :
                  .defective replication
                  .pairing of alkylguanine with thymine, and
  then substitution of At for GC
                  .Excision of guanine and chain breakage.
The principal effect occurs during DNA synthesis.
                             Contd
• Unwanted effects include myelosuppression, sterility and risk of non-
  lymphocytic leukaemia.
• The main alkylating agents are: Nitrogen mustards: e.g
  cyclophosphamide, which is activated to give aldophosphamide, which
  is then converted to phosphoramide mustard and acrolein.
  Cyclophosphamide myelosuppression affects particularly the
  lymphocytes. Given orally.
• Nitrosoureas: e.g lomustine may act on non-dividing cells;can cross
  the blood-brain barrier; causes delayed, cumulative
  myelotoxicity.Given orally.
• Cisplatin; It interacts with DNA;it has low myelotoxicity but causes
  severe nausea and vomiting and can be nephrotoxic. Given
  intravenously.
Anticancer drugs: antimetabolites
• These drugs block or subvert pathways in DNA synthesis.
• Folate antagonists: Methotrexate inhibits dihydrofolate
  reductase, preventing generation of tetrahydrofolate; the
  main result is interference with thymidylate synthesis.
  Methotrexate is taken up into cells by the folate carrier,
  and like folate, converted to the polyglutamate form. Given
  orally. Normal cells affected by high doses can be rescued
  by folinic acid.(Folate—FH2---FH4----MethyleneFH4—
  Deoxythymidylic acid Methionine)
  Unwanted effects: myelosuppression,possible
  nephrotoxicity.
                         Contd
• Pyrimidine analogues: Fluorouracil, given orally or
  intravenously, is converted to a fraudulent nucleotide and
  inhibits thymidylate synthesis.
• Cytarabine, given intravenously or subcutaneously; its
  triphosphate form inhibits DNA polymerase; potent
  myelosuppressive.
• Purine analogues: Mercaptopurine, given orally, is
  converted into a fraudulent nucleotide.
      Anticancer drugs: cytotoxic
              antibiotics
• Doxorubicin : It inhibits DNA and RNA synthesis; the DNA effect is
  due to interference with topoisomerase ll action. Given by intravenous
  infusion; it is excreted mainly in bile. Unwanted effects: nausea and
  vomiting, myelosuppression, hair loss; it is cardiotoxic in high doses.
• Biomycin: It causes fragmentation of DNA chains. It can act on non-
  dividing cells. Given by injection. Unwanted effects: fever,allergies,
  pulmonary fibrosis. Virtually no myelosuppression.
• Dactinomycin: It intercalates in DNA, interferes with RNA
  polymerase and inhibits transcription. Given by injection. Unwanted
  effects: nausea and vomiting, myelosuppression.
• Mitomycin : It is activated to give an alkylating metabolite. Given
  intravenously.
 Anticancer drugs: miscellaneous
             agents
• Plant alkaloids: Vincristine It inhibits mitosis at
  metaphase by binding to tubulin. Given by injection.
  Relatively non-toxic, but can cause unwanted
  neuromuscular effects.
• Hormones: These are used in hormone-sensitive tumours:
  Glucocorticoids for leukaemias and
  lymphomas.Oestrogens for tumours in men. Androgens
  or tamoxifen for breast tumours.
• Radioactive isotopes: It can be targeted at specific
  tissuese. E.g I 131 for thyroid tumours.
                     Leukemia
• Malignant disorders of blood leukocytes.
• Support the patient with red cell and platelet
  transfusion.
• Remission induction chemotherapy and
  maintenance chemotherapy.
• Remission induction chemotherapy: The objective is
  to clear the body of all detectable leukemic leukocytes.
  The current practise is to employ a combination of
  vincristine and prednisone for initial induction of
  remission.
                         Contd
• Maintenance Chemotherapy: The objective of
  maintenance therapy is to keep the population of residual
  leukemic cells in check so that they do not repopulate the
  blood and bone marrow and lead to the return of
  symptoms.
• This usually consists of a combination of oral
  methortrexate, mercaptopurine and cyclophosphamide,
  administered either in pulses, simultaneously, or in various
  sequences.
          Treatment for HBV
• HBV infected persons should be evaluated by
  their doctor for liver disease.
• Adefovir dipivoxil, interferon alfa-2b,
  pegylated interferon alfa-2a, lamivudine, and
  entecavir are five drugs used for the
  treatment of persons with chronic hepatitis B.
• These drugs should not be used by pregnant
  women.
• Drinking alcohol can make your liver disease
  worse.

				
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posted:8/6/2011
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