156
G. Yang and Y. Huang
expanded AS1411’s phase 1 clinical trials as a monotherapy in patients with renal
cell carcinoma and in combination with cytarabine in patients with refractory or
recurrent acute myeloid leukemia. The results showed that cancer was significantly
suppressed or disappeared in at least three patients with renal cell carcinoma and four
patients with acute myeloid leukemia. However, the phase 2b trial of AS1411 was
terminated due to the suspension of drug development by Antisoma [197]. Advanced
Cancer Therapeutics has not conducted further clinical trials after renaming AS1411
to ACTGro-777.
AS1411 has good safety and long-lasting therapeutic effect. However, there are
still some deficiencies in the pharmacology and potency of unmodified AS1411, and
chemical modification is needed to improve its performance. Fan et al. [198] reported
a variant of AS1411 modified by 2
-deoxyinosine, which can significantly inhibit
DNA replication and cancer cell growth, and induce S-phase cell cycle arrest. Furthermore, AS1411 [77] was modified with 2-deoxyinosine (2
-Di) and D-mercaptan Lisothiouracil (D-/L-isot) to improve the affinity of aptamer to the target and inhibit
the growth of tumor cells in vitro. The partial base 5
-(N-naphthylformamide)-2
-
(deoxyuridine) modified AS1411 and designed by Cho et al. [199] significantly
inhibited the proliferation of hepatocellular carcinoma cells.
AS1411 is used as a targeting element for the targeted delivery of a variety of
drugs, including chemical drugs, chitosan, conditioned responsive micellar polymers, dendrimer polymers, silicon nanoparticles, GO-based nanoparticles, AuNPs,
AgNCs, serum albumin nanoparticles, nucleic acid drugs, liposome, niosome, and
so on (Table 6.3).
6.5.2.2 Aptamers Targeting EGFR/ErbB
Epidermal growth factor-associated protein (ErbB) family receptor tyrosine kinase
plays an important role in epitheliogenesis and has become a major therapeutic target
for many kinds of cancers. ErbB-1 (also known as epidermal growth factor receptor
(EGFR) or HER-1) and ErbB-4 share some ligands, but no similar ErbB-2 ligands
have been found. Overexpression and mutation of ErbB family members lead to
the occurrence of many kinds of malignant tumors [232]. So far, several anti-ErbB
specific aptamers [176, 225, 233–235] have been developed. The aptamers of ErbB1/EGFR and ErbB-3/HER3 can inhibit the proliferation of cancer cells in vitro [176,
225] and in vivo [234].
ErbB-1/EGFR
Epidermal growth factor receptor (EGFR) is associated with a variety of cancers,
including breast cancer, glioma, lung cancer, and liver cancer [236]. Therefore,
neutralizing EGFR signals by blocking EGFR binding sites in the extracellular
domain can limit the growth of EGFR positive tumors, so a variety of EGFR inhibitors
have been approved for cancer therapy, including monoclonal antibodies (cetuximab
and necitumumab) and small molecule inhibitors (erlotinib hydrochloride). However,
the application of these EGFR inhibitors has been limited by toxicity and acquired
G. Yang and Y. Huang
expanded AS1411’s phase 1 clinical trials as a monotherapy in patients with renal
cell carcinoma and in combination with cytarabine in patients with refractory or
recurrent acute myeloid leukemia. The results showed that cancer was significantly
suppressed or disappeared in at least three patients with renal cell carcinoma and four
patients with acute myeloid leukemia. However, the phase 2b trial of AS1411 was
terminated due to the suspension of drug development by Antisoma [197]. Advanced
Cancer Therapeutics has not conducted further clinical trials after renaming AS1411
to ACTGro-777.
AS1411 has good safety and long-lasting therapeutic effect. However, there are
still some deficiencies in the pharmacology and potency of unmodified AS1411, and
chemical modification is needed to improve its performance. Fan et al. [198] reported
a variant of AS1411 modified by 2
-deoxyinosine, which can significantly inhibit
DNA replication and cancer cell growth, and induce S-phase cell cycle arrest. Furthermore, AS1411 [77] was modified with 2-deoxyinosine (2
-Di) and D-mercaptan Lisothiouracil (D-/L-isot) to improve the affinity of aptamer to the target and inhibit
the growth of tumor cells in vitro. The partial base 5
-(N-naphthylformamide)-2
-
(deoxyuridine) modified AS1411 and designed by Cho et al. [199] significantly
inhibited the proliferation of hepatocellular carcinoma cells.
AS1411 is used as a targeting element for the targeted delivery of a variety of
drugs, including chemical drugs, chitosan, conditioned responsive micellar polymers, dendrimer polymers, silicon nanoparticles, GO-based nanoparticles, AuNPs,
AgNCs, serum albumin nanoparticles, nucleic acid drugs, liposome, niosome, and
so on (Table 6.3).
6.5.2.2 Aptamers Targeting EGFR/ErbB
Epidermal growth factor-associated protein (ErbB) family receptor tyrosine kinase
plays an important role in epitheliogenesis and has become a major therapeutic target
for many kinds of cancers. ErbB-1 (also known as epidermal growth factor receptor
(EGFR) or HER-1) and ErbB-4 share some ligands, but no similar ErbB-2 ligands
have been found. Overexpression and mutation of ErbB family members lead to
the occurrence of many kinds of malignant tumors [232]. So far, several anti-ErbB
specific aptamers [176, 225, 233–235] have been developed. The aptamers of ErbB1/EGFR and ErbB-3/HER3 can inhibit the proliferation of cancer cells in vitro [176,
225] and in vivo [234].
ErbB-1/EGFR
Epidermal growth factor receptor (EGFR) is associated with a variety of cancers,
including breast cancer, glioma, lung cancer, and liver cancer [236]. Therefore,
neutralizing EGFR signals by blocking EGFR binding sites in the extracellular
domain can limit the growth of EGFR positive tumors, so a variety of EGFR inhibitors
have been approved for cancer therapy, including monoclonal antibodies (cetuximab
and necitumumab) and small molecule inhibitors (erlotinib hydrochloride). However,
the application of these EGFR inhibitors has been limited by toxicity and acquired