Anticancer Drugs

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Anticancer Drugs

• Felix Hernandez, M.D.

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Alkylating Agents

• The first anticancer agents developed
• Chemically related to mustard gas used in WW1
• Are more effective in treating slow-growing
  tumors because they are cell-cycle nonspecific
• Alkylating agent induced damage to cancer cells
  accumulates even during non-active portions of
  the cell cycle.
• All alkylating agents are toxic to hematologic
  cells, therefore myelosuppression is a
  predictable side effect
• The drugs used to treat CNS cancers are used
  because they cross the BBB not because they are
  better agents

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Alkylating Agents

• Chlorambucil
• Phase non specific
• MOA crosslinks DNA by binding to both strands
• Resistance decreased cellular uptake and
  increased repair of drug induced DNA damage
• Side Effects bone marrow suppression, drug is
  carcinogenic and may be teratogenic
• Indications Chronic Lymphocytic Leukemia (CLL),
  Ovarian Carcinoma
• Cyclophosphamide
• Phase non specfic
• MOA metabolized to phosphoramide mustard which
  is a DNA alkylating agent
• Resistance same
• Side Effects hemorrhagic cystitis, BM
  suppression, cardiotoxicity
• Administer Mensa to prevent hemorrhagic cystitis
  (binds to the toxic metabolite)
• Indications breast, testicular and other solid
  tumors, leukemia, lymphoma, neuroblastoma and
  immunosuppression

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Alkylating Agents

• Carmustine
• Phase non specific
• MOA inhibit DNA synthesis by DNA alkylation and
  protein carbamoylation
• Resistance Same
• Side Effects bone marrow suppression, pulmonary
  toxicity
• Indications CNS tumors, lymphomas, Hodgkins,
  melanoma
• Cisplastin
• Phase non specific
• MOA crosslinks DNA
• Resistance Same
• Side Effects renal toxicity, BM suppression,
  ototoxicity
• Use Amifostine to bind the toxic metabolites and
  decrease the nephrotoxicity
• Indications testicular, ovarian, lung, bladder
  cancer, neuroblastoma, brain tumors, and
  osteosarcoma

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Antimetabolites

• Are cell cycle specific agents
• Prevent the synthesis of nucleotides or inhibit
  enzymes by mimicking nucleotides
• Methotrexate
• Mercaptopurine
• 5-Fluorouracil (5-FU)

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Antimetabolites

• Methotrexate
• Phase S-phase. It also arrests some cells in G1
  phase and stop them from entering S-phase
• MOA blocks folate reduction by inhibiting
  dihydrofolate reductase.
• Resistance decreased uptake, increased
  production of dihydrofolate reductase, altered
  forms of DHFR
• Side Effects BM suppression, GI ulcers,
  nephrotoxicity, hepatotoxicity
• Give leucovorin with it to rescue folate in
  noncancerous cells
• Indications Acute Lymphocytic Leukemia (ALL),
  osteogenic sarcoma, breast, head neck, small cell
  lung, psoriasis, and RA

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Antimetabolites

• Mercaptopurine
• Phase S-phase
• MOA metabolized to 6-mercaptopurine ribose
  phosphate (6MPRP), a false negative feedback
  inhibitor
• Resistance increased alkaline phosphatase which
  degrades 6MPRP, decreased sensitivity to feedback
  inhibition
• Side Effects BM suppression, hepatotoxicity
• Indications Acute leukemia

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Antimetabolites

• 5-Fluorouracil (5-FU)
• Phase S/G1 phase-specific
• MOA metabolized to fluoro-UMP which incorporates
  into RNA. Is also metabolized to fluoro-dUMP
  which inhibits thymidylate synthetase
• Prodrugs are Floxuridine and Capecitabine
• Resistance decreased phosphorylation of the
  prodrug to active form, increased or altered
  target enzyme
• Side Effects anorexia, ulcers, BM suppression,
  dermatitis, photo-sensitivity
• Indications Many solid tumors, topically for
  superficial tumors of the skin, Floxuridine for
  GI adenocarcinoma and Capecitabine for breast CA

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Antibiotic Cancer Agents

• Are isolated from the fungal species Streptomyces
• Dactinomycin
• Phase S-phase
• MOA intercalates between guanine bases of DNA.
  Also decreases RNA synthesis by blocking
  DNA-dependent RNA synthesis
• Resistance Decreased drug uptake
• Side Effects hypersensitivity, BM suppression,
  ulcers, acne, injection site necrosis
• Indications Wilms tumor, Ewing Sarcoma,
  testicular tumors

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Antibiotic Cancer Agents

• Doxorubicin (Adriamycin), Daunorubicin
  (Daunomycin)
• Phase S-phase
• MOA Intercalates into DNA and decreases DNA and
  RNA synthesis, causes single and double strand
  breaks
• Resistance decreased drug uptake, increased drug
  efflux
• Side Effects irreversible cardiomyopathy which
  leads to CHF, ECG changes (benign), leukopenia
• Give Dexrazone to reduce the cardiomyopathy
• Indications Doxorubicin ? sarcomas, multiple
  myeloma, acute leukemias, testicular, breast,
  gastric, bladder, and throat CA. Daunorubicin ?
  Acute leukemias

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Antibiotic Cancer Agents

• Bleomycin
• Phase G2/M-Phase-Specific
• MOA Bithiazole rings intercalate into DNA
  strands. The drugs also oxidizes iron creating
  free radicals which damage DNA
• Side Effects pulmonary fibrosis, pneumonitis,
  ulceration, increased skin pigmentation
• Indications testicular cancer, lymphomas, SCC of
  the head, neck, skin and genitalia.
• Is also used as a sclerosing agent for malignant
  pleural effusion

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Mitosis Inhibitors

• Vincristine, Vinblastine
• Phase M-phase
• MOA binds tubulin and depolymerizes microtubules
• Resistance decreased drug uptake and retention
• Side Effects autonomic, peripheral and motor
  neuropathy, no BM Suppression
• Indications
• Vincrsitine ALL, Hodgkins
• Vinblastine Lymphomas
• Isolated from the periwinkle plant

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Mitosis Inhibitors

• Paclitaxel
• Phase M-phase specific
• MOA stabalizes microtubules and prevents the
  depolymerize microtubules which is essential for
  mitosis
• Side Effects peripheral neuropathy, BM
  suppression, myalgias
• Indications metastatic ovarian carcinoma, breast
  CA
• Isolated from the bark of western yew
• Etoposide
• Phase G2-phase-specific
• MOA interferes with topoisomerase which causes
  DNA strand breaks
• Side Effects BM suppression
• Indications testicular and lung cancers

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Others

• Hydroxyurea
• Phase S-phase-specific
• MOA inhibits ribonucleotide reductases therefor
  blocking deoxyribonucleotide formation (DNA
  nucleotides)
• Side Effects BM suppression
• Indications chronic granulocytic leukemia
• Topotecan
• Phase Non specific
• MOA interacts with topoisomerase I and results
  in DNA breaks during replication
• Side Effects BM suppression, severe diarrhea
• Indications lung and ovarian CA

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Monoclonal Antibodies

• Rituxamab
• MOA binds CD20 antigen on B-cells found in
  B-cell lymphomas and it exerts its cytotoxicity
• Side Effects chills, rigors (infusion related)
• Indications B-cell lymphomas
• Trastuzumab
• MOA binds to HER2 protein and inhibits the
  growth of tumor cells
• HER2 is overexpressed in 20-30 of breast CA
• Side Effects same as Rituxamab
• Indications Breast CA

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Hormones

• Tamoxifen
• MOA Estrogen receptor antagonist that prevents
  endogenous estrogens from stimulating tumor
  growth
• Indications estrogen-receptor positive breast CA
  in postmenopausal women
• Side Effects increased risk of uterine CA in
  treated women
• Aromatase Inhibitor
• MOA inhibits aromatase, the enzyme responsible
  for estrogen production in the ovaries
• Indications advanced breast CA
• Flutamide
• MOA testosterone receptors antagonist
• Indications to inhibit the transient side
  effects caused by initial Leuprolide induced LH
  and FSH secretion

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Hormones

• Leuprolide
• MOA GNRH analog which desensitizes GNRH
  receptors in the pituitary causing a decreased
  release of gonadotropin. Results in a decrease in
  sex hormone release
• Indications advanced prostate CA
• Side Effects initially stimulates a transient
  release of FSH and LH

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Immune Mediators

• Interferon
• MOA enhances the activity of cytotoxic-T, NK
  cells, and macrophages. Inhibits the
  proliferation of tumor cells.
• Indications Hairy cell leukemia, Kaposis
  Sarcoma
• Misc.
• Tretinoin
• MOA analog of retinoic acid (vitamin A) and
  induces maturation in acute promyelocytic
  leukemia cells and neuroblastoma.
• Side Effects retinoic acid syndrome (fever,
  dyspnea, pulmonary infiltrates and effusions,
  fluid retention)

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Hematopoetic Agents

• Epoetin Alpha (Epogen)
• MOA recombinant human erythropoetin that
  stimulates erythropoiesis
• Indications anemia associated with CRF,
  correcting AZT (Zidovudine) induced anemia, and
  chemotherapy induced anemia
• Requires several weeks of therapy before a change
  in H/H is seen. It doesnt replace transfusion
  for acute treatments
• Contraindicated in patients with uncontrolled HTN
  because it can exacerbate the HTN with the rise
  in hematocrit

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Hematopoetic Agents

• Filgrastim (G-CSF)
• MOA recombinant granulocyte colony stimulating
  factor which induces the synthesis of neutrophils
• Indications replenishment of neutrophils in
  patients treated with myelosuppressive drugs
• Side Effects medullary bone pain due to rapid
  cell proliferation in the BM
• Sargramostim (GM-CSF)
• MOA recombinant granulocyte-macrophage colony
  stimulating factor. Induces the maturation
  granulocytes and macrophages but nor erythrocytes
  or megakaryocytes,
• Indications accelerate BM replenishment
  following BM transplantation
• Side Effects Medullary bone pain