ANTINEOPLASTIC

• Cancer - Characteristics: 


  – Infinite dividing cancer cells

  – Lack of growth controls

  – Ability to invade local tissues

  – Ability to spread
• TYPES OF CANCER

  -solid tumors

  -hematologic malignancies
• SOLID TUMORS 


  Carcinomas (epithelial cells)

  Sarcoma (connective tissues)
• EMATOLOGIC MALIGNANCIES 


  Lymphoma (lymphatic system)

  Leukemia (blood-forming elements)
• New or unusual growth of tissue tumors. May be benign or malignant

  NEOPLASMS
• Total eradication of cancer cells; Lower tumor cell burden at which level host immunological defenses may keep the cells in control

  CURATIVE .
•  Alleviation of symptoms, decrease tumor size, control growth. Avoidance of life-threatening toxicity. Increased survival and improved quality of life

  PALLIATIVE 
• Attempt to eradicate microscopic cancer after surgery

  ADJUVANT THERAPY
• an attempt to get a patient into remission, after previous therapies have failed

  SALVAGE CHEMOTHERAPY
• Chemotherapy is given to decrease the tumor burden before definitive therapy (surgery, radiation)

  NEOADJUVANT
• chemotherapeutic agents kill a constant fraction of cells (first order kinetics), rather than a specific number of cells, after each dose.


  LOG KILL HYPOTHESIS 
• Synthesis of cellular component needed for DNA synthesis

  G1
• Replication of DNA genome (DNA synthesis)

  S
• Growth and preparation for mitosis

  G2
• (Mitosis) Cell division and cell differentiation

  M
• MOA: Alkylation – replacement of hydrogen ion in an atom with an alkyl, inhibition of DNA replication DNA is unable to replicate X cell proliferation cell death

  ALKYLATING AGENTS
• For Hodgkin’s lymphoma, mycosis fungoides (cutaneous T- cell lymphoma – A di-alkylating agent such that one mustard can alkylate two nucleophiles

  MECHLORETHAMINE
• Treatment for Hodgkin’s lymphoma and chronic lymphocytic leukemia with prednisone

  CHLORAMBUCIL (LEUKERAN)
• 2mg tablets for multiple myeloma, breat and ovarian cancer — 50-mg IV when bone marrow transplant if being utilized


  MELPHALAN (ALKERAN)
• treatment of a wide variety of cancers, including breast cancer, non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, ovarian cancer; ell cycle–nonspecific

  CYCLOPHOSPHAMIDE
• third-line therapy in the treatment of testicular cancer

  IFOSFAMIDE
• treatment of bladder cancer, ovarian cancer, and breast cancer • AE: dose-limiting myelosuppression and mucositis

  THIOTEPA (THIOPLEX)
• 4-5 alkyl substituents- optimal for antineoplastic activity; tx of chronic myelogenous leukemia (CML) and in high-dose therapy for refractory

  BUSULFAN (MYLERAN)
• AE: dose-limiting myelosuppression; nausea and vomiting; and pulmonary symptoms including interstitial pulmonary fibrosis or “busulfan lung,”

  BUSULFAN (MYLERAN)
• N-methyl-N-nitroguanidine as having activity – chemical decomposition was leading to the formation of diazomethane (CH2N2) and subsequent alkylation

  Nitrosoureas
• Undergo spontaneous non-enzymatic degradation with the formation of the 2-chloroethyl carbonium ion from diazohydroxide formed

  Nitrosoureas
• Liberates isocyanate that attach carbamoyl groups to the lysine residues of proteins- inactivate DNA

  Nitrosoureas
• Carmustine

  BCNU (Bis-Chloroethyl nitrosourea)
• Lomustine (Medac)


  CCNU (Chloroethyl-Cyclohexyl nitrosourea)
• primary and metastatic brain cancers and Hodgkin’s lymphoma

  LOMUSTINE
• treatment of metastatic islet cell carcinoma of the pancreas, colon cancer, and Hodgkin’s disease. presence of the glucose moiety allows for utilization of glucose transporters, which concentrate the compound in the β-cells of the pancreas

  Streptozocin
• • thought to act as an inhibitor of purine biosynthesis, but latter was shown to be an alkylating agent
  • CYP mediated activation, tautomerization allows formation of diazomethane

  Dacarbazine
• • antineoplastic agent that was originally developed as a result of efforts to find new inhibitors of monoamine oxidase 


  Procarbazine
• • CYP/monoamine oxidase mediated oxidation occurs in the liver to give azo-procarbazine

  Procarbazine
• is the dose-limiting toxicity for all drugs in this class. (Antimetabolites)

  Myelosuppression
• • MOA: inh of purine biosynthesis
  • Major pathway for inactivation is through S- Methylation by TPMT- Thiopurine-S- methyl transferase) and through oxidation by XO- Xanthine Oxidase.


  6-Mercaptopurine, Thioguanine
• • the thiol analog of hypoxanthine
  • requires bioactivation to its ribonucleotide, 6-thioinosinate (6-MPMP), by the enzyme HGPRT: The ribose diphosphate and triphosphates of 6-mercaptopurine are active enzyme inhibitors, and the triphosphate can be incorporated into DNA and RNA to inhibit chain elongation.

  6-Mercaptopurine, Thioguanine
• derivative of 6-Mercaptopurine, is used as an immunosuppressive agent. has antitumor activity, it is not significantly better than 6- mercaptopurine.

  Azathioprine
• is converted into a 'fraudulent' nucleotide, fluorodeoxyuridine monophosphate (FdUMP).


  Fluorouracil
•  is the first choice for the treatment of colon cancer.

  5-FU