A Comprehensive Monograph on Chlorambucil (DB00291): Chemistry, Pharmacology, and Clinical Application

I. Executive Monograph: Chlorambucil (DB00291)

Overview

Chlorambucil, identified by DrugBank ID DB00291, is a small molecule chemotherapeutic agent belonging to the nitrogen mustard class of alkylating drugs.[1] First synthesized in 1953 and granted FDA approval in 1957, it represents one of the foundational oral chemotherapy drugs developed in the 20th century.[3] It functions as a bifunctional, cell cycle phase-nonspecific alkylating agent, meaning it can exert its cytotoxic effects on cancer cells regardless of their stage in the cell division cycle.[6]

Core Mechanism

The primary mechanism of action for chlorambucil is the alkylation of DNA.[1] Upon entering a cell, it forms a highly reactive ethylenimonium radical that covalently binds to nucleophilic sites on DNA, with a preference for the N7 position of guanine bases.[6] As a bifunctional agent with two reactive chloroethyl arms, it can form both intrastrand and interstrand DNA cross-links.[8] These cross-links physically prevent the unwinding and separation of the DNA double helix, thereby inhibiting critical cellular processes like DNA replication and RNA transcription. This irreparable damage triggers cellular surveillance mechanisms, leading to cell cycle arrest and ultimately apoptosis (programmed cell death).[1]

Primary Indications

Chlorambucil is primarily indicated for the treatment of various hematologic malignancies.[1] Its approved uses include:

• Chronic Lymphocytic Leukemia (CLL) [2]
• Hodgkin's Lymphoma [2]
• Non-Hodgkin's Lymphomas, including lymphosarcoma and giant follicular lymphoma [1]
• Waldenström's Macroglobulinemia [1]

Critical Safety Profile