1. Introduction
Alkylating agents are one of the oldest and most widely used classes of anticancer drugs.
They act primarily by adding alkyl groups to DNA bases, leading to cross-linking, strand breakage, and inhibition of DNA replication and transcription, ultimately triggering cell death.
These drugs are cell cycle–nonspecific, meaning they can act in all phases of the cell cycle, but rapidly dividing cells (such as cancer cells) are most affected.
Alkylating agents are used in the treatment of lymphomas, leukemias, solid tumors, and brain cancers.
2. Mechanism of Action
- Alkylating agents transfer alkyl groups (-CH₂-) to nucleophilic sites in DNA, particularly at the N7 position of guanine.
- This leads to:
- Mispairing during replication
- Cross-linking of DNA strands (intra- and inter-strand)
- DNA fragmentation and inhibition of repair enzymes
- Cell cycle arrest and apoptosis
Because they are nonspecific for the cell cycle, both dividing and resting cells can be affected, contributing to both therapeutic effects and toxicity.
3. Classification
| Category | Examples | Clinical Notes |
|---|---|---|
| Nitrogen mustards | Mechlorethamine, Cyclophosphamide, Ifosfamide, Melphalan, Chlorambucil | Most common class; used in lymphomas, leukemias, and breast cancer |
| Nitrosoureas | Carmustine (BCNU), Lomustine (CCNU), Streptozocin | Lipophilic – cross blood-brain barrier; used in brain tumors |
| Alkyl sulfonates | Busulfan | Specific for chronic myeloid leukemia (CML) |
| Triazenes | Dacarbazine, Temozolomide | Used in melanoma and glioblastoma |
| Ethylenimines & methylmelamines | Thiotepa, Altretamine | Used in ovarian and breast cancers |
| Platinum analogs (alkylating-like) | Cisplatin, Carboplatin, Oxaliplatin | Form DNA cross-links but do not add true alkyl groups; used in solid tumors |
4. Pharmacokinetics Overview
| Drug | Route | Activation | Elimination |
|---|---|---|---|
| Cyclophosphamide | Oral, IV | Hepatic activation (CYP2B6, CYP3A4) | Renal |
| Ifosfamide | IV | Hepatic activation | Renal |
| Melphalan | Oral, IV | Direct active | Renal |
| Busulfan | Oral, IV | Direct active | Hepatic (GSH conjugation) |
| Carmustine | IV | Spontaneous activation | Renal |
| Dacarbazine | IV | Hepatic activation | Renal |
| Temozolomide | Oral | Spontaneous activation at physiologic pH | Renal |
5. Clinical Uses
a. Hematologic Malignancies
- Hodgkin’s lymphoma (e.g., mechlorethamine in MOPP regimen)
- Non-Hodgkin’s lymphoma
- Multiple myeloma (melphalan)
- Chronic myeloid leukemia (busulfan)
b. Solid Tumors
- Breast cancer (cyclophosphamide)
- Ovarian and testicular cancers (ifosfamide, cisplatin)
- Brain tumors (nitrosoureas, temozolomide)
- Melanoma (dacarbazine)
c. Conditioning Regimens
- High-dose alkylators (cyclophosphamide, busulfan) used before bone marrow transplantation
6. Toxicity Profile
A. Hematologic Toxicity
- Myelosuppression (dose-limiting): leukopenia, thrombocytopenia, anemia
- May cause pancytopenia in high doses
- Secondary acute myeloid leukemia (AML) risk increases with prolonged use
B. Gastrointestinal
- Nausea, vomiting, mucositis
- Treatable with 5-HT3 antagonists (ondansetron, granisetron)
C. Reproductive
- Gonadal toxicity → amenorrhea, oligospermia, infertility
D. Specific Drug Toxicities
| Drug | Unique Toxicities | Prevention/Notes |
|---|---|---|
| Cyclophosphamide / Ifosfamide | Hemorrhagic cystitis due to acrolein metabolite | Use Mesna (2-mercaptoethanesulfonate) and hydration |
| Busulfan | Pulmonary fibrosis (“Busulfan lung”) | Monitor lung function |
| Cisplatin | Nephrotoxicity, ototoxicity, neurotoxicity | Prevent with hydration and Amifostine |
| Nitrosoureas | CNS toxicity (confusion, ataxia) | Cross BBB; used in brain tumors |
| Dacarbazine / Temozolomide | Flu-like symptoms, hepatic toxicity | Temozolomide better tolerated orally |
7. Mechanisms of Resistance
Cancer cells may develop resistance via:
- Increased DNA repair (O⁶-methylguanine-DNA methyltransferase, MGMT)
- Increased glutathione and detoxifying enzymes
- Decreased drug uptake or increased efflux
- Mutations in apoptotic pathways
Clinical strategy: Combine alkylating agents with other drug classes (antimetabolites, topoisomerase inhibitors) to minimize resistance.
8. Clinical Considerations
- Myelosuppression monitoring: CBC weekly
- Renal and hepatic function tests: before each cycle
- Hydration and Mesna prophylaxis with cyclophosphamide or ifosfamide
- Fertility counseling: cryopreservation recommended
- Tumor lysis syndrome prophylaxis in high-tumor-burden cases (with allopurinol)
9. Summary Table
| Class | Examples | Main Uses | Major Toxicity |
|---|---|---|---|
| Nitrogen mustards | Cyclophosphamide, Ifosfamide | Lymphoma, breast cancer | Myelosuppression, cystitis |
| Nitrosoureas | Carmustine, Lomustine | Brain tumors | CNS toxicity |
| Alkyl sulfonates | Busulfan | CML, bone marrow prep | Pulmonary fibrosis |
| Triazenes | Dacarbazine, Temozolomide | Melanoma, glioma | Hepatic, myelosuppression |
| Platinum analogs | Cisplatin, Carboplatin | Solid tumors | Nephrotoxicity, ototoxicity |
10. Summary
Alkylating agents remain foundational in cancer chemotherapy due to their broad spectrum of activity and ability to destroy rapidly dividing cells.
However, their dose-limiting toxicities — particularly myelosuppression and secondary malignancies — necessitate careful monitoring and supportive care.
Modern practice integrates alkylating agents in combination regimens, dose-modified protocols, and targeted delivery systems to optimize efficacy while minimizing systemic toxicity.
11. References
- Chabner BA, Longo DL. Cancer Chemotherapy and Biotherapy: Principles and Practice. 7th ed. Lippincott Williams & Wilkins; 2022.
- Brunton LL, Knollmann BC, Hilal-Dandan R. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14th Edition, 2021.
- DeVita VT Jr, et al. Cancer: Principles & Practice of Oncology. 12th ed. Wolters Kluwer, 2023.
- National Cancer Institute. Chemotherapy Types: Alkylating Agents.
- NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Hodgkin Lymphoma, Breast Cancer, CNS Cancers.
- Lenz HJ. Mechanisms of drug resistance in chemotherapy. Semin Oncol. 2013;40(5):526–532.
