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Biersack. Cancer Drug Resist 2019;2:1-17 I http://dx.doi.org/10.20517/cdr.2019.09 Page 3

Figure 1. Structures of the N-mustard alkylating agents melphalan, chlorambucil, cyclophosphamide and estramustine

[21]
which plays a crucial role for the cellular response to DNA damage . The tumor suppressor microRNA
miR-34a is connected with p53-signaling and low expression of miR-34a led to chemoresistance in CLL . A
[22]
considerable number of PCLBCL-LT (primary cutaneous diffuse large B-cell lymphomas, leg-type) patients
did not respond to chlorambucil first-line therapy and upregulated expression of the oncogenic miR-17-92
[23]
cluster seems responsible leading to suppression of PTEN (phosphatase and TENsin homolog) . A miR-210
targeting/inhibiting chlorambucil conjugate was synthesized, which suppressed a cancer relevant hypoxic
[24]
mechanism and was active against hypoxic triple-negative breast cancer in mice . A list of miRNAs
associated with chlorambucil activity is provided in Table 1.

Melphalan is a close analog of chlorambucil and has been applied for the treatment of multiple myeloma
[25]
(MM) since the 1960’s . From MM patients treated with melphalan circulating exosomal let-7b and miR-
[26]
18a were identified as prognostic factors (i.e., improved survival) . Suppression of the oncogenes Myc,
Ras and CCND1 (cyclin D1) by let-7b may play a role as well as inhibition of the HIF1α-pathway [hypoxia-
inducible factor (HIF)] by miR-18a . IL-6-mediated downregulation of the tumor suppressor miR-
[26]
[27]
15a/16 expression increased resistance of myeloma cells to melphalan treatment . The oncogenic miR-
221-222 family suppressed p53 upregulated modulator of apoptosis (PUMA) in MM cells leading to drug
[28]
resistance . Inhibition of miR-221 by a 13 mer LNA-i-miR-221 inhibitor broke melphalan resistance in MM
[29]
by modulation of PUMA (upregulation) and ATP binding cassette C1 (ABCC1) transporter (downregulation) . In
addition, it was suggested that suppression of miR-451 can enhance the activity of melphalan in multiple
[30]
myeloma via downregulation of multidrug resistance gene 1 (MDR1) . A list of miRNAs involved in
melphalan activity in myeloma is given in Table 2.

Cyclophosphamide is one of the most successful anticancer drugs which is still widely applied for the
[31]
therapy of many cancer diseases 60 years now after its development in the late 1950’s . The drug is applied
[31]
for the treatment of breast cancer, childhood cancers, and lymphoma . Cyclophosphamide is a prodrug,
which can be activated in a chemical or metabolic way. Enzymatic oxidation of cyclophosphamide generates
cytotoxic phosphoramide mustard molecules leading to interstrand and intrastrand crosslinks of DNA as
well as toxic acrolein which is responsible for the side effects of cyclophosphamide .
[32]