finals topic ORG MED

• Ultimate goal in cancer chemotherapy

  Use advances in cell biology to develop drugs that selectively target specific cancer cells
• Anticancer drugs

  • Alkylating agents
  • Antimetabolites
  • Natural Products
  • Antitumor Antibiotics
  • Miscellaneous
  • Hormonal
• Alkylating agents

  • Cyclophosphamide
  • Cisplatin
• What drugs are under this Antimetabolites

  • 5-FU
  • Methotrexate
  • Gemcitabine
  • 6-mercaptopurine
• Natural Products

  • Etoposide
  • Paclitaxel
  • Vincristine
• Antitumor Antibiotics

  • Belomycin
  • Doxorubicin
  • Mitomycin
• Miscellaneous

  • Imatinib
  • Cetuximab
• Hormonal

  • Prednisone
  • Tamoxifen
• Mechanisms of resistance to anticancer drugs

  • Increased DNA repair
  • Formation of trapping agents
  • Changes in target enzymes
  • Decreased activation of prodrugs
  • Inactivation of anticancer drugs
  • Decreased drug accumulation
• Cell cycle-specific (CCS) drugs


  Exert their actions selectively on cycling cells
• Cell cycle-nonspecific (CCNS) drugs


  Kill tumor cells in both cycling and resting phases of the cell cycle (although cycling cells are more sensitive)
• Log-kill hypothesis


  Proposes that the magnitude of tumor cell kill by anticancer drugs is a logarithmic function
• Cancer treatment modalities

  • Primary induction chemotherapy
  • Neoadjuvant chemotherapy
  • Adjuvant chemotherapy
• Leucovorin


  A form of tetrahydrofolate that is accumulated more readily by normal than by neoplastic cells, bypasses the dihydrofolate reductase step in folic acid synthesis, administered for the toxicity with high doses of Methotrexate
• Mercaptoethanesulfonate (mesna)


  Traps acrolein released from cyclophosphamide, reduces the incidence of hemorrhagic cystitis
• Dexrazoxane


  Inhibits free radical formation, affords protection against the cardiac toxicity of anthracyclines
• Alkylating agents


  • Nitrogen mustards (chlorambucil, cyclophosphamide, mechlorethamine)
  • Nitrosoureas (carmustine, lomustine)
  • Alkyl sulfonates (busulfan)
  • Others (cisplatin, dacarbazine, procarbazine)
• Alkylating agents


  • Form reactive molecular species that alkylate nucleophilic groups on DNA bases, particularly the N-7 position of guanine, leading to crosslinking of bases, abnormal base-pairing, and DNA strand breakage
• Tumor cell resistance to alkylating agents

  Increased DNA repair, decreased drug permeability, production of trapping agents (thiols)
• Cyclophosphamide


  1. P450-mediated biotransformation is needed for antitumor activity

  2. One of the breakdown products - acrolein
• Uses of cyclophosphamide


  • Leukemia
  • Non-Hodgkin's lymphoma
  • Breast and ovarian cancers
  • Neuroblastoma
• Adverse effects of cyclophosphamide

  • Gastrointestinal distress
  • Myelosuppression
  • Alopecia
  • Hemorrhagic cystitis
  • Cardiac dysfunction
  • Pulmonary toxicity
  • SIADH
• Mechlorethamine


  Spontaneously converts in the body to a reactive cytotoxic product
• Uses of mechlorethamine


  • Hodgkin's
• Toxicity of mechlorethamine


  • Gastrointestinal distress
  • Mild hematotoxicity
  • Neurotoxic (peripheral neuritis, acoustic nerve damage)
  • Nephrotoxity
• Carboplatin


  Less nephrotoxic than cisplatin, less likely to cause tinnitus and hearing loss, has greater myelosuppressant actions
• Oxaliplatin


  Dose-limiting neurotoxicity
• Procarbazine


  Forms hydrogen peroxide, generates free radicals that cause DNA strand scission, orally active, penetrates into most tissues including the cerebrospinal fluid, hepatic elimination
• Uses of procarbazine


  • Non-Hodgkin's lymphoma
• Toxicity of procarbazine


  • Gastrointestinal distress
  • Myelosuppression
  • Alopecia
  • Sterility
• Toxicity of BCNU and CCNU

  • Myelosuppressant - leukemogenic
  • Gastrointestinal irritation
  • CNS dysfunction
  • Vesicant (blister-forming)
  • Peripheral neuropathy
• Busulfan


  Used in chronic myelogenous leukemia, causes adrenal insufficiency, pulmonary fibrosis, skin pigmentation
• Carmustine and Lomustine


  Adjuncts in the management of brain tumors
• Dacarbazine


  Used in regimens for Hodgkin's lymphoma, adverse effects include alopecia, skin rash, gastrointestinal distress, myelosuppression, phototoxicity, flu-like syndrome
• Antimetabolites


  • Antagonists of folic acid (methotrexate)
  • Purines (mercaptopurine, thioguanine)
  • Pyrimidines (fluorouracil, cytarabine, gemcitabine)
• Antimetabolites


  CCS drugs acting primarily in the S phase of the cell cycle, exert cytotoxic effects on neoplastic cells, have immunosuppressant actions
• Methotrexate


  Inhibitor of dihydrofolate reductase, leads to a decrease in the synthesis of thymidylate, purine nucleotides, and amino acids, interferes with nucleic acid and protein metabolism, formation of polyglutamate derivatives important for cytotoxic actions
• Uses of methotrexate


  • Non-Hodgkin's and primary central nervous system lymphomas
  • Solid tumors
  • Rheumatoid arthritis
  • Psoriasis
  • Ectopic pregnancy
• Toxicity of methotrexate


  • Bone marrow suppression
  • Skin and mucositis
  • Hepatotoxicity
  • Pulmonary infiltrates and fibrosis
• Leucovorin rescue


  Folinic acid, reduces toxic effects of methotrexate