Nursing Pharmacology:  Anticancer Drugs: Antibiotics

• 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 --

  • Carcinomas-Doxorubicin

    •  Breast carcinoma

    •  Endometrial carcinoma

    •  Ovarian carcinoma

    •  Testicular carcinoma

    •  Thyroid carcinoma

    •  Lung carcinoma

  • Sarcomas-Doxorubicin

    • Ewing's sarcoma

    • Osteosarcoma

    • Rhabdomyosarcomas

  • Hematologic Cancers-Doxorubicin

    •  Acute leukemia

    •  Multiple myeloma

    •  Hodgkin's disease

    •  Non-Hodgkin's lymphoma

  • 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 of 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.