• Clinically useful anticancer antibiotics: derived from Streptomyces

• These antibiotics act by:
  • DNA intercalation, blocking synthesis of DNA and RNA

• Anthracyclines: Doxorubicin (Adriamycin, Rubex, Doxil) and Daunorubicin (DaunoXome)
  • IV administration; hepatic metabolism; biliary excretion; some urinary excretion; enterohepatic recirculation.
  • Among the most useful anticancer antibiotics
  • Mechanism of action:
    • DNA intercalation -- blocking synthesis of DNA and RNA; DNA strands scission -- by affecting topoisomerase II
    • Altering membrane fluidity and ion transport
    • Semiquinone free radical an oxygen radical generation (may be responsible for myocardial damage)

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• Clinical Uses:
  • Doxorubicin (Adriamycin, Rubex, Doxil)-- very important anticancer agent --

• Adjuvant therapy in: osteogenic sarcoma and breast cancer
• Generally used in combination protocols with:
  • cyclophosphamide (Cytoxan)
  • cisplatin (Platinol)
  • nitrosoureas
• Major Use: Acute Leukemia
• Daunorubicin: limited utility-- limited efficacy in treating solid tumors.
• Idarubicin: approved for acute myeloid leukemia
  • Idarubicin in combination with cytarabine: more active than daunorubicin in inducing complete remission in acute myelogenous leukemia.
•  Adverse Effects:
  • Bone marrow depression (short duration)
  • Cumulative, dose-related, possibly irreversible cardiotoxicity.
  • Total, severe alopecia

• Dactinomycin (Cosmegen)

  • IV administration; 50 percent remains unmetabolized.

  • Mechanism of action: intercalation between guanine-cytosine base pairs

    • inhibits DNA-dependent RNA synthesis

    • blocks protein synthesis

  • Clinical Uses:

    • dactinomycin in combination with vincristine (Oncovin)and surgery (may include radiotherapy) in treatment of Wilms' tumor

    • dactinomycin with methotrexate: maybe curative for localized or disseminated gestational choriocarcinoma.

  •  Adverse Effects:

    •  Major dose limiting toxicity: bone marrow suppression (all blood elements affected -- particularly platelets and leukocytes)

      • occasional severe thrombocytopenia

    • nausea

    • vomiting

    • diarrhea

    • oral ulcers

    • Dactinomycin: immunosuppressive (patient should not receive live virus vaccines)

    • alopecia/skin abnormalities

    • interaction with radiation ("radiation recall")

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• Plicamycin (Mithramycin)

• Mechanism of action:binds to DNA -- interrupts DNA-directed RNA synthesis

  • Also decreases plasma calcium (independent tumor cell action;acts on osteoclasts)

• Clinical Uses:

  • some efficacy in testicular cancer that is unresponsive to standard treatment:

  • especially useful in managing severe hypercalcemia associated with cancer

•  Adverse Effects:

  • nausea

  • vomiting

  • thrombocytopenia

  • leukopenia

  • hypocalcemia

  • liver toxicity

  • bleeding disorders

• Mitomycin: (Mutamycin)

  • Mechanism of action:

    • metabolic activation to produce a DNA alkylating agent.

    • Solid tumor hypoxic stem cells may be more sensitive to the action of mitomycin.

    • Best available drug, in combination with x-rays, to kill hypoxic tumor cells.

  •  Clinical Use:

    • in combination chemotherapy {with vincristine and bleomycin}: squamous sell carcinoma of the cervix

    • adenocarcinoma of the stomach, pancreas, and lung {along with flurouracil and doxorubicin}

    • second-line drug: metastatic colon cancer

    • topical intravesical treatment of small bladder papillomas.

  •  Adverse Effects:

    •  severe myelosuppression, especially after repeated doses, suggest action on hematopoietic stem cells.

    • Vomiting

    • anorexia

    • occasional nephrotoxicity

    • occasional interstitial pneumonitis

• Bleomycin (Blenoxane)

• Mechanism of Action:binds to DNA -- produces single- and double-strand breaks (free radical formation)

  • Cell cycle specific: arrests division in G2

  • Synergistic effects with vinblastine and cisplatin (curative protocol for testicular cancer)

• Clinical Uses:

  • Testicular cancer

  • Squamous cell carcinoma: head, neck, cervix, skin, penis, and rectum

  • combination treatment: lymphoma

  • intracavity treatment: malignant effusions in ovarian breast cancer

•  Adverse Effects:

  • Anaphylactoid reaction (potentially fatal)

  • Fever

  • anorexia, blistering, hyperkeratosis (palms)

  • pulmonary fibrosis (uncommon)

  • No significant myelosuppression

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