Chlorambucil

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Background

Chlorambucil is a nitrogen mustard alkylating agent [1]
Chlorambucil is a chemotherapy medication commonly used for the treatment of chronic lymphocytic leukemia (CLL). Chlorambucil forms intra- and inter-strand crosslinks in DNA, the latter of which prevents DNA replication and transcription leading to cell death [1]
In embryonic mouse limb buds directly exposed to chlorambucil at 1 ~ 2 μg/mL, the number of affected cells reached a plateau at 48 hr after treatment and decreased significantly by 72 hr, at which time exposure to a second dose of chlorambucil showed little or no effect. Chlorambucil-induced cell death was restricted almost exclusively to regions of undifferentiated mesenchymal cells [2].
In CLL patients, chlorambucil treatment (0.9 mg/kg given over 3 days) induced greater decrease in lymphocyte count against the control group [3]. In pharmacokinetic studies in tumor-bearing dogs receiving 4 mg/m2 metronomic chlorambucil, the LD50 and IC50 of chlorambucil were 270 μM and 114 μM for SF767 cells, and 390 μM and 96 μM for U87-MG cells, respectively. In human microvascular endothelial cells and human progenitor derived endothelial colony forming cells, the IC50 of chlorambucil was 0.53 μM and 145 μM, correspondingly [4].

[1]. Mattes W B, Hartley J A, Kohn K W. DNA sequence selectivity of guanine-N7 alkylation by nitrogen mustards. Nucleic Acids Research, 1986, 14(7): 2971-2987.
[2]. Sadler T W, Kochhar D M. Chlorambucil-induced cell death in embryonic mouse limb buds. Toxicology and Applied Pharmacology, 1976, 37(2): 237-256.
[3]. Begleiter A, Lee K, Israels L G, et al. Chlorambucil induced apoptosis in chronic lymphocytic leukemia (CLL) and its relationship to clinical efficacy. Leukemia, 1994, 8(1): S103-S106.
[4]. Reese M J, Knapp D W, Anderson K M, et al. In vitro effect of chlorambucil on human glioma cell lines (SF767 and U87-MG), and human microvascular endothelial cell (HMVEC) and endothelial progenitor cells (ECFCs), in the context of plasma chlorambucil concentrations in tumor-bearing dogs. PLoS One, 2018, 13(9): e0203517.