Antibiotics / antineoplastics

Introduction

The use of antibiotics as antineoplastic agents represents one of the most significant breakthroughs in oncology. While antibiotics are commonly associated with the treatment of bacterial infections, certain naturally derived or semi-synthetic antibiotics possess potent anticancer properties. These drugs do not act primarily through antibacterial mechanisms; instead, they interfere with DNA replication, RNA synthesis, or cellular enzymes critical for tumor cell survival and proliferation.

The group collectively referred to as antibiotics/antineoplastics includes drugs such as anthracyclines, bleomycin, mitomycin, dactinomycin, and others, all derived originally from Streptomyces species or related microorganisms. They are primarily employed in chemotherapy protocols for hematologic malignancies, breast cancer, sarcomas, testicular cancer, lymphomas, and many solid tumors.

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Classification of Antibiotics / Antineoplastics

The group can be classified into several major subclasses:

1. Anthracyclines

   • Doxorubicin

   • Daunorubicin

   • Epirubicin

   • Idarubicin

   • Valrubicin

2. Bleomycin

3. Dactinomycin (Actinomycin D)

4. Mitomycin C

5. Miscellaneous agents with antibiotic origin but antitumor activity

   • Plicamycin (Mithramycin, rarely used due to toxicity)

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Mechanism of Action

1. Anthracyclines (Doxorubicin, Daunorubicin, Epirubicin, Idarubicin, Valrubicin)

• DNA Intercalation: Insert between DNA base pairs, disrupting replication and transcription.

• Topoisomerase II Inhibition: Prevents religation of DNA strands, leading to double-strand breaks.

• Free Radical Generation: Produces reactive oxygen species (ROS), causing oxidative damage to cellular structures.

2. Bleomycin

• Binds DNA and generates free radicals, leading to strand scission.

• Strongly active during the G2 phase of the cell cycle.

3. Dactinomycin (Actinomycin D)

• Intercalates between guanine-cytosine DNA base pairs.

• Inhibits RNA polymerase, suppressing transcription.

4. Mitomycin C

• A bioreductive alkylating agent.

• Cross-links DNA, preventing replication.

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Clinical Uses

Anthracyclines

• Doxorubicin: Breast cancer, Hodgkin’s and non-Hodgkin’s lymphomas, sarcomas, leukemias, ovarian cancer.

• Daunorubicin: Acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL).

• Epirubicin: Breast cancer, gastric cancer, lung cancer.

• Idarubicin: AML, ALL (often in combination regimens).

• Valrubicin: Intravesical therapy for bladder cancer refractory to BCG.

Bleomycin

• Hodgkin’s lymphoma (ABVD regimen).

• Testicular cancer (BEP regimen).

• Head and neck cancers.

Dactinomycin (Actinomycin D)

• Wilms’ tumor.

• Rhabdomyosarcoma.

• Gestational trophoblastic neoplasia (choriocarcinoma).

Mitomycin C

• Gastric cancer.

• Pancreatic cancer.

• Bladder cancer (intravesical instillation).

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Generic Names and Doses

Doxorubicin

• IV: 60–75 mg/m² every 21 days (single agent).

• Or 40–60 mg/m² every 21–28 days in combination therapy.

• Lifetime cumulative dose: 450–550 mg/m² (due to cardiotoxicity risk).

Daunorubicin

• IV: 45 mg/m²/day for 1–3 days in AML induction regimens.

• In ALL: 25–45 mg/m²/day for 1–3 days.

Epirubicin

• IV: 60–120 mg/m² every 3–4 weeks.

• Maximum cumulative dose: 900 mg/m².

Idarubicin

• IV: 12 mg/m²/day for 3 days in AML induction therapy.

Valrubicin

• Intravesical: 800 mg once weekly for 6 weeks.

Bleomycin

• IV/IM/Subcutaneous: 10–20 units/m² weekly, or 30 units IV every 3 weeks.

• Cumulative dose should not exceed 400 units (due to pulmonary toxicity).

Dactinomycin (Actinomycin D)

• IV: 0.5–1.25 mg/m² daily for 1–5 days, depending on protocol.

Mitomycin C

• IV: 10–20 mg/m² every 6–8 weeks.

• Intravesical: 20–40 mg weekly for bladder cancer.

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Adverse Effects

Anthracyclines

• Cardiotoxicity (dose-dependent, may manifest as heart failure).

• Myelosuppression.

• Alopecia.

• Mucositis.

• Secondary leukemia (rare).

Bleomycin

• Pulmonary fibrosis (dose-limiting toxicity).

• Skin hyperpigmentation.

• Minimal myelosuppression.

Dactinomycin

• Severe myelosuppression.

• Mucositis.

• Hepatotoxicity.

Mitomycin C

• Myelosuppression.

• Hemolytic-uremic syndrome (rare, but serious).

• Pulmonary fibrosis (at high doses).

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Contraindications

• Severe myelosuppression.

• Cardiac impairment (anthracyclines contraindicated).

• Pulmonary fibrosis or impaired lung function (bleomycin contraindicated).

• Pregnancy and breastfeeding.

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Precautions

• Cumulative dose monitoring for anthracyclines (due to cardiotoxicity).

• Pulmonary function testing prior to bleomycin therapy.

• Careful hydration and renal monitoring with mitomycin.

• Strict aseptic technique (extravasation of anthracyclines causes severe local necrosis).

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Drug Interactions

• Anthracyclines + Trastuzumab: Increased risk of cardiotoxicity.

• Bleomycin + Oxygen therapy: Exacerbated pulmonary toxicity.

• Mitomycin + Alkylating agents: Enhanced risk of myelosuppression.

• CYP450 inducers/inhibitors: May alter metabolism of anthracyclines.

• Live vaccines: Avoid due to immunosuppression.

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Clinical Efficacy and Limitations

Antibiotics/antineoplastics are among the most effective chemotherapeutic agents. Anthracyclines, for example, are central to protocols like CHOP for non-Hodgkin lymphoma and ABVD for Hodgkin’s lymphoma. However, their long-term use is limited by cumulative toxicities (cardiac for anthracyclines, pulmonary for bleomycin).

Their use requires rigorous dosing schedules, precise monitoring of organ function, and often combination therapy with other cytotoxic agents to enhance efficacy while minimizing resistance.