Alkylating agents

Introduction

Alkylating agents are one of the oldest and most widely used classes of antineoplastic (anticancer) drugs. They act by adding alkyl groups to cellular macromolecules, particularly DNA, thereby interfering with cell replication and transcription. Their discovery dates back to the World War II era, when nitrogen mustards, initially developed as chemical warfare agents, were observed to cause bone marrow suppression. This finding led to their adaptation as chemotherapeutic drugs, marking the beginning of modern cancer chemotherapy.

These agents are used across a wide range of hematological malignancies (e.g., lymphomas, leukemias, multiple myeloma) and solid tumors (e.g., breast, ovarian, testicular, and brain cancers). Although highly effective, their therapeutic window is narrow, and toxicity—especially myelosuppression, infertility, and secondary malignancies—remains a major concern.

Mechanism of Action

Alkylating agents act by covalently binding alkyl groups to nucleophilic sites within DNA bases. This leads to:

1. DNA cross-linking (intra- and inter-strand) → prevents strand separation, blocking replication and transcription.

2. Abnormal base pairing and miscoding → leads to mutations and apoptosis.

3. DNA strand breaks → further inhibiting cell survival.

Unlike many cytotoxic drugs, alkylating agents are cell cycle–nonspecific; they act in all phases of the cell cycle, though rapidly dividing cells (cancer cells, bone marrow, gastrointestinal mucosa, hair follicles) are most sensitive.

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Classification of Alkylating Agents

1. Nitrogen Mustards

   • Examples: Cyclophosphamide, Ifosfamide, Mechlorethamine, Melphalan, Chlorambucil.

2. Nitrosoureas

   • Examples: Carmustine (BCNU), Lomustine (CCNU), Streptozocin.

3. Alkyl Sulfonates

   • Example: Busulfan.

4. Triazenes and Hydrazines

   • Examples: Dacarbazine, Temozolomide, Procarbazine.

5. Ethylenimines and Methylmelamines

   • Examples: Thiotepa, Altretamine.

6. Platinum analogs (alkylating-like agents)

   • Examples: Cisplatin, Carboplatin, Oxaliplatin.

   • Strictly speaking, these are not alkylating agents but exert similar effects by forming DNA cross-links.

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Therapeutic Uses

• Hematological Malignancies

  • Hodgkin and non-Hodgkin lymphomas (cyclophosphamide, procarbazine, mechlorethamine).

  • Multiple myeloma (melphalan, cyclophosphamide).

  • Leukemias (busulfan for chronic myeloid leukemia, cyclophosphamide for acute leukemias).

• Solid Tumors

  • Breast cancer (cyclophosphamide).

  • Ovarian cancer (carboplatin, cisplatin).

  • Testicular cancer (cisplatin-based regimens).

  • Brain tumors (temozolomide, carmustine, lomustine).

• Conditioning for Stem Cell Transplant

  • High-dose cyclophosphamide, busulfan, melphalan, thiotepa used as part of pre-transplant regimens.

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Common Alkylating Agents: Generic Names and Typical Doses

1. Cyclophosphamide (Nitrogen Mustard)

• Uses: Breast cancer, lymphomas, leukemias, ovarian cancer, nephrotic syndrome (immunosuppressive).

• Doses:

  • IV: 500–1500 mg/m² every 3 weeks (cancer regimens).

  • Oral: 1–5 mg/kg daily (immunosuppressive).

2. Ifosfamide (Nitrogen Mustard)

• Uses: Testicular cancer, sarcomas, lymphomas.

• Dose: 1.2 g/m² IV daily for 5 days every 3 weeks.

• Requires mesna co-administration to prevent hemorrhagic cystitis.

3. Mechlorethamine (Mustine)

• Uses: Hodgkin lymphoma (MOPP regimen).

• Dose: 6 mg/m² IV every 4 weeks.

4. Melphalan

• Uses: Multiple myeloma, ovarian cancer.

• Dose: 0.15 mg/kg/day orally for 4 days (myeloma).

5. Chlorambucil

• Uses: Chronic lymphocytic leukemia (CLL), lymphomas.

• Dose: 0.1–0.2 mg/kg orally daily.

6. Busulfan (Alkyl Sulfonate)

• Uses: Chronic myeloid leukemia (historical), conditioning for stem cell transplant.

• Dose: 0.8 mg/kg IV every 6 hours for 4 days (transplant conditioning).

7. Carmustine (BCNU) (Nitrosourea)

• Uses: Brain tumors, lymphomas.

• Dose: 150–200 mg/m² IV every 6 weeks.

8. Lomustine (CCNU) (Nitrosourea)

• Uses: Brain tumors, Hodgkin lymphoma (second-line).

• Dose: 100–130 mg/m² orally every 6 weeks.

9. Streptozocin

• Uses: Pancreatic neuroendocrine tumors.

• Dose: 500 mg/m² IV daily for 5 days every 6 weeks.

10. Dacarbazine (DTIC) (Triazene)

• Uses: Hodgkin lymphoma, melanoma, sarcomas.

• Dose: 150–250 mg/m² IV daily for 5 days every 3 weeks.

11. Temozolomide (Oral Triazene)

• Uses: Glioblastoma multiforme, anaplastic astrocytoma.

• Dose: 150–200 mg/m² orally daily for 5 days every 28 days.

12. Procarbazine (Hydrazine derivative)

• Uses: Hodgkin lymphoma (MOPP regimen), brain tumors.

• Dose: 100 mg/m² orally daily for 14 days.

13. Thiotepa (Ethylenimine)

• Uses: Ovarian cancer, breast cancer, bladder cancer (intravesical), conditioning for transplant.

• Dose: 0.3–0.4 mg/kg IV every 1–4 weeks.

14. Altretamine (Methylmelamine)

• Uses: Ovarian cancer refractory to first-line therapy.

• Dose: 260 mg/m²/day orally in divided doses for 14–21 days of a 28-day cycle.

15. Platinum Analogs (Alkylating-like Agents)

• Cisplatin: 50–100 mg/m² IV every 3–4 weeks (testicular, ovarian, bladder cancer).

• Carboplatin: Dosed using Calvert formula: Dose (mg) = Target AUC × (GFR + 25).

• Oxaliplatin: 85 mg/m² IV every 2 weeks (colorectal cancer).

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Contraindications

• Pregnancy and lactation (teratogenic, mutagenic).

• Severe bone marrow suppression.

• Hypersensitivity to the drug.

• Severe hepatic or renal impairment (for drugs metabolized or excreted via these organs).

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Side Effects

Common Adverse Effects

• Myelosuppression (dose-limiting for most agents).

• Nausea and vomiting (especially with cisplatin, dacarbazine).

• Alopecia.

• Mucositis.

Specific Adverse Effects

• Cyclophosphamide, Ifosfamide: Hemorrhagic cystitis (prevented with mesna and hydration).

• Busulfan: Pulmonary fibrosis (“busulfan lung”), adrenal insufficiency, seizures.

• Cisplatin: Nephrotoxicity, ototoxicity, severe nausea.

• Carboplatin: Myelosuppression (less nephrotoxic).

• Oxaliplatin: Peripheral neuropathy (cold-induced).

• Procarbazine: MAOI-like activity (interacts with tyramine foods, causing hypertensive crisis).

• Nitrosoureas: Delayed myelosuppression, neurotoxicity.

Long-term Risks

• Infertility (gonadal toxicity).

• Secondary malignancies (especially acute myeloid leukemia).

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Precautions

• Prehydration and diuretics for cisplatin to prevent nephrotoxicity.

• Mesna prophylaxis for cyclophosphamide and ifosfamide.

• Antiemetics (5-HT3 antagonists, NK1 antagonists) to control nausea.

• Fertility counseling before treatment (consider sperm/egg preservation).

• Close monitoring of CBC, renal function, and liver function.

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Drug Interactions

1. Allopurinol – increases toxicity of cyclophosphamide.

2. Warfarin – increased anticoagulant effect with cyclophosphamide, procarbazine.

3. Live vaccines – contraindicated due to immunosuppression.

4. Nephrotoxic drugs (aminoglycosides, amphotericin B) – worsen cisplatin nephrotoxicity.

5. Other bone marrow suppressants – additive risk of severe cytopenias.

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Clinical Considerations

• Combination Chemotherapy: Alkylating agents are almost always used in combination regimens (e.g., CHOP, MOPP, BEP, ABVD) to enhance efficacy and reduce resistance.

• Resistance Mechanisms: Increased DNA repair, decreased drug uptake, increased glutathione conjugation.

• Individualized Dosing: Many agents (e.g., carboplatin) require renal function-based dosing to balance efficacy and toxicity.

• Supportive Care: Prophylactic growth factors (G-CSF), transfusions, and infection prophylaxis may be needed during therapy.