General Features
- Subclass of alkylating agents (cell cycle–nonspecific).
- Highly lipophilic → readily cross the blood–brain barrier (BBB) → particularly useful in CNS malignancies.
- Mechanism: Alkylation → DNA interstrand cross-links, inhibition of DNA/RNA synthesis, cell death.
- Pharmacology: Delayed myelosuppression (nadir 4–6 weeks, recovery 6–8 weeks).
- Major cumulative toxicity: Pulmonary fibrosis and organ toxicities (renal, hepatic).
Key Agents
| Drug | Route | Uses | Dose & Schedule | Unique Points | Toxicities (Key) |
|---|---|---|---|---|---|
| Carmustine (BCNU) | IV, also Gliadel® wafers (implant) | Brain tumors, HL/NHL, conditioning (BEAM) | 150–200 mg/m² IV q6w | First nitrosourea; wafer form for local brain therapy | Delayed myelosuppression, pulmonary fibrosis (cumulative >1400 mg/m²), hepatotoxicity, nephrotoxicity, highly emetogenic |
| Lomustine (CCNU) | Oral | Brain tumors, HL salvage | 100–130 mg/m² PO q6–8w | Oral bioavailability, used in gliomas | Same as BCNU: delayed myelosuppression, pulmonary fibrosis (>1100 mg/m² cumulative), hepatotoxicity, nephrotoxicity |
| Semustine (MeCCNU) | Oral | Brain & GI tumors (historical, rarely used) | 100–150 mg/m² PO q6w | Related to lomustine; limited today due to carcinogenicity | Same + high leukemogenic/carcinogenic risk |
| Streptozocin (Zanosar®) | IV | Pancreatic neuroendocrine tumors (islet cell carcinoma) | 500 mg/m²/day ×5 q6w or 1000 mg/m² q3w | Sugar moiety → selective uptake in pancreatic β-cells | Nephrotoxicity (dose-limiting), severe N/V, mild myelosuppression, hepatotoxicity |
| Fotemustine (Europe, not widely in NA) | IV | Brain metastases (esp. melanoma), gliomas | 100 mg/m² weekly ×3, then q3w | Lipophilic, active in melanoma CNS mets | Myelosuppression, pulmonary toxicity |
Monitoring for All Nitrosoureas
- CBC weekly for 6 weeks post-dose.
- Pulmonary function tests (baseline and periodic).
- Renal & liver function tests.
- Track cumulative dose to avoid pulmonary fibrosis.
Summary:
Nitrosoureas are alkylating agents with excellent CNS penetration, making them key in treating brain tumors and some lymphomas. Their hallmark is delayed myelosuppression and cumulative pulmonary, renal, and hepatic toxicities. Carmustine and Lomustine remain clinically relevant, Streptozocin is mainly for pancreatic NETs, while Semustine is largely obsolete due to carcinogenicity.