Regarding alkylating agents used in cancer chemotherapy, all of the following statements are correct EXCEPT:

Question

Accepted Answer

D. Busulfan is the alkylating agent of choice for chronic myeloid leukemia and causes minimal myelosuppression. ## Analysis of Alkylating Agents

### Correct Statements

**Option 1: Cyclophosphamide Activation**
- Cyclophosphamide is a **prodrug** that undergoes hepatic metabolism via cytochrome P450 (primarily CYP2C9 and CYP3A4)
- Converted to active metabolites including phosphoramide mustard and acrolein
- [cite:KD Tripathi Ch 65]

**Option 2: Nitrogen Mustards and DNA Cross-linking**
- Nitrogen mustards (mechlorethamine, cyclophosphamide, ifosfamide) form **inter-strand DNA cross-links**
- Covalent bonding between guanine residues on opposite DNA strands prevents replication and transcription
- This is the primary mechanism of cell death

**Option 4: Nitrosoureas and CNS Penetration**
- Nitrosoureas (carmustine, lomustine) are **highly lipophilic**
- Readily cross the blood-brain barrier due to their lipophilicity
- Used for brain tumors and CNS lymphomas
- [cite:Harrison 21e Ch 96]

### Incorrect Statement (The Answer)

**Option 3: Busulfan and Myelosuppression**
- Busulfan is an alkylating agent used in CML and as a conditioning agent for bone marrow transplantation
- However, busulfan causes **SEVERE myelosuppression** — not minimal
- Dose-limiting toxicity is bone marrow suppression
- Also causes pulmonary fibrosis ("busulfan lung") and hepatic veno-occlusive disease (VOD)
- [cite:KD Tripathi Ch 65]

**Key Point:**

Busulfan is notorious for **profound myelosuppression** and requires careful monitoring of blood counts. It is NOT sparing of the bone marrow.

**High-Yield:**

Alkylating agents share a common mechanism: formation of DNA cross-links. However, their toxicity profiles differ — busulfan's major toxicity is myelosuppression, while cyclophosphamide's is hemorrhagic cystitis (acrolein metabolite) and mesna is used as a uroprotective agent.

**Clinical Pearl:**

When busulfan is used in high doses for stem cell transplantation conditioning, it requires close monitoring and supportive care due to the risk of hepatic VOD, which can be life-threatening.

Answer

A. Nitrogen mustards cause cross-linking of DNA by forming covalent bonds between complementary strands

Answer

B. Cyclophosphamide requires hepatic activation by cytochrome P450 enzymes to form active metabolites

Answer

C. Nitrosoureas are lipophilic and can cross the blood-brain barrier, making them useful in CNS lymphomas

Regarding alkylating agents used in cancer chemotherapy, all of the following statements are correct EXCEPT:

Explanation

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