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)

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")

• 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

Salmon, S. E. and Sartorelli, A. C. Cancer Chemotherapy, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p. 881-911.