Alkylating Agents - DNA's Sticky Attackers
- Mechanism: Covalently attach alkyl groups to DNA bases.
- Primarily targets N7 position of guanine.
- Can also alkylate N1 & N3 of adenine, N3 of cytosine.
- Consequences:
- DNA strand breakage (due to unstable alkylated bases).
- Abnormal base pairing (e.g., G-T instead of G-C).
- Formation of DNA cross-links (intrastrand or interstrand).
- Interstrand cross-links are particularly cytotoxic, preventing DNA separation for replication/transcription.
- Cell Cycle Specificity:
⭐ Alkylating agents are cell cycle phase-nonspecific but are most effective against rapidly dividing cells.
- Overall Effect: Disrupt DNA replication & transcription → apoptosis.
Classes & Examples - The Alkylating Lineup
| Class | Prototype Drug(s) | Key Feature/Unique Point |
|---|---|---|
| Nitrogen Mustards | Cyclophosphamide, Ifosfamide, Melphalan, Chlorambucil | Prodrugs (Cyclo, Ifos); Acrolein (hemorrhagic cystitis - MESNA); Oral (Melphalan, Chlorambucil) |
| Nitrosoureas | Carmustine (BCNU), Lomustine (CCNU), Streptozocin | Highly lipid-soluble, cross BBB; Streptozocin: pancreatic islet cell tumors |
| Alkyl Sulfonates | Busulfan | Selective myelosuppression; "Busulfan lung" (pulmonary fibrosis), adrenal insufficiency |
| Triazenes | Dacarbazine, Temozolomide | Dacarbazine (IV); Temozolomide (Oral, CNS penetration, glioblastoma) |
| Platinum Analogs | Cisplatin, Carboplatin, Oxaliplatin | DNA binding; Cisplatin (nephro/ototoxicity); Carboplatin (myelosuppression); Oxaliplatin (cold neurotoxicity) |
Clinical Corner - Targeting Tumors
- Cyclophosphamide: Broad use in lymphomas (NHL), leukemias, breast & ovarian Ca, neuroblastoma.
⭐ Cyclophosphamide is a key component of many combination chemotherapy regimens, including CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone) for non-Hodgkin lymphoma.
- Ifosfamide: Testicular Ca, sarcomas.
- Platinum Analogs:
- Cisplatin: Testicular, ovarian, bladder, lung, head & neck Ca.
- Carboplatin: Ovarian, lung Ca; preferred for ↓nephrotoxicity.
- Oxaliplatin: Colorectal Ca (part of FOLFOX regimen).
- Nitrosoureas (e.g., Carmustine, Lomustine): Brain tumors (glioblastoma, astrocytoma) due to BBB penetration.
- Temozolomide: Glioblastoma multiforme, anaplastic astrocytoma.
- Busulfan: CML (historically); conditioning for bone marrow transplant (BMT).
- Melphalan: Multiple myeloma, ovarian Ca.
- Dacarbazine (DTIC): Hodgkin lymphoma (ABVD regimen), metastatic melanoma.
Toxic Terrors & Defenses - Side Effects & Resistance
- Common: Myelosuppression (dose-limiting), Nausea/Vomiting, Alopecia, Infertility.
- Secondary Malignancies (e.g., AML/MDS).
| Drug | Specific Toxicity | Management/Prevention |
|---|---|---|
| Cyclophosphamide/Ifosfamide | Hemorrhagic cystitis (acrolein) | Mesna, hyperhydration |
| Cisplatin | Nephrotoxicity, Ototoxicity, Peripheral neuropathy | Amifostine, hydration |
| Carboplatin | Myelosuppression (thrombocytopenia) | Dose adjust, supportive care |
| Busulfan | Pulmonary fibrosis, VOD, Seizures | Prophylactic anticonvulsants, monitor |
| Nitrosoureas (CCNU, BCNU) | Delayed myelosuppression, Pulmonary fibrosis | Monitor |
⭐ Mesna prevents hemorrhagic cystitis with cyclophosphamide/ifosfamide by neutralizing acrolein in the bladder.
- Resistance Mechanisms:
- ↑ DNA repair (e.g., ↑MGMT).
- ↓ Drug uptake / ↑ efflux (e.g., P-gp).
- ↑ Inactivation by glutathione.
High‑Yield Points - ⚡ Biggest Takeaways
- Alkylating agents covalently bind DNA (N7-guanine), causing cross-links & cell death.
- Cell cycle non-specific (CCNS); most effective in late G1/S phase.
- Cyclophosphamide/Ifosfamide: Hemorrhagic cystitis (acrolein); prevent with MESNA & hydration.
- Cisplatin: Nephrotoxicity (use Amifostine), ototoxicity, peripheral neuropathy, severe emesis.
- Nitrosoureas (Carmustine, Lomustine): Lipophilic, cross BBB; treat brain tumors.
- Major toxicities: Dose-limiting myelosuppression, ↑risk of secondary cancers (e.g., AML).
- Busulfan: Pulmonary fibrosis ("Busulfan lung"), skin hyperpigmentation.
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