428
H. Jin
due to their unique physical, chemical, and biological properties. Therefore, aptamer
technology has been widely investigated for biomedical and clinical applications.
The following part will focus on the potential applications of aptamer technology as
a new tool for the precision treatment of hematological malignancies.
Hematological malignancies are a collection of heterogeneous neoplasm arising
from cells of the bone marrow and lymphatic system. There are three major groups of
hematological malignancies, i.e., leukemia, lymphoma, and plasma cell neoplasms
among which leukemia ranks sixth in the lifetime cost of cancer. Chemotherapy is
the mainstay treatment for hematological malignancies [134]. Compared with traditional therapy based on the antibody, aptamer provides higher tissue permeability.
It can penetrate cell membranes and reach its target more efficiently; the simpler
structure suitable for modifying with low cost enables aptamer to be optimized for
its clinical properties; lack of immunogens also eliminates the possibility of toxicity
of chemotherapy. The advances in aptamer-based target therapy are rendering them
as powerful tools of hematological malignancies.
AS1411, an ssDNA aptamer targeting nucleolin of cancer cells, is the first aptamer
to undergo Phase I clinical trials initiated in 2003 with advanced solid tumors and
proved to be safe without serious toxicity [99]. In the Phase 2 study [135], 44
patient with relapsed/refractory acute myeloid leukemia provide the safety results
across the groups, 21 to AS1411 10 mg/kg/day plus high-dose cytarabine (HiDAC)
(AS1411–10), 9 to AS1411 40 mg/kg/day plusHiDAC (AS1411–40) and 14 to
HiDAC alone (control). The most common toxicities were hematologic, notably
febrile neutropenia, neutropenia, thrombocytopenia, and infections. Except that
grade 3 hypokalemia was more frequent with AS1411–40. Deaths within 28 days
of treatment were AS1411–10, 1/21; AS1411–40, 1/9; and control, 2/14. Response
rates from 39 patients were AS1411–10, 16% (3/19); AS1411–40, 14% (1/7); and
control, 0% (0/13). Data from the clinical trial present the promising signs of the
combination of AS1411 at 10 or 40 mg/kg/day with HiDACto treat patients with
relapsed/refractory AML. No further clinical trial performed on AS1411, because of
the right transform of AS1411 to the Advanced Cancer Therapeutics and renamed
as ACT-GRO-777 [136].
Rosenberg [104] also showed AS1411’s potential in treating acute myeloid
leukemia in combination with cytarabine with less toxicity and special effects.
Both Sgc-8 aptamers (88-mer) [137–139] and its truncated form scg8c (41-mer)
can be internalized into target cells vis receptor-mediated endocytosis. Scg8c specifically targets protein tyrosine kinase-7, which is highly expressed on the membrane
of T-acute lymphoblastic leukemia (ALL) cells, Scg8c can work as capable vehicles to carry drug and targets biomarker on hematopoietic cells, Huang et al. [140]
conjugate Dox to aptamer Sgc8c-7 to accurately deliver and internalize Dox into
CCRF-CEM cells (a T-ALL cell line).
N0XA-12 is an RNA aptamer, acts as the specific antagonist of CXCL12 which can
disrupt the binding of CXCL12 to CXCR4, decline homing and retention of chronic
lymphoblastic leukemia (CLL) cells in bone marrow, and enhance the chemotherapy
and trigger apoptosis of CLL cells in peripheral blood. In a completed phase 2 clinical study on NOX-A12, 28 patients with relapsed/refractory chronic lymphocytic
H. Jin
due to their unique physical, chemical, and biological properties. Therefore, aptamer
technology has been widely investigated for biomedical and clinical applications.
The following part will focus on the potential applications of aptamer technology as
a new tool for the precision treatment of hematological malignancies.
Hematological malignancies are a collection of heterogeneous neoplasm arising
from cells of the bone marrow and lymphatic system. There are three major groups of
hematological malignancies, i.e., leukemia, lymphoma, and plasma cell neoplasms
among which leukemia ranks sixth in the lifetime cost of cancer. Chemotherapy is
the mainstay treatment for hematological malignancies [134]. Compared with traditional therapy based on the antibody, aptamer provides higher tissue permeability.
It can penetrate cell membranes and reach its target more efficiently; the simpler
structure suitable for modifying with low cost enables aptamer to be optimized for
its clinical properties; lack of immunogens also eliminates the possibility of toxicity
of chemotherapy. The advances in aptamer-based target therapy are rendering them
as powerful tools of hematological malignancies.
AS1411, an ssDNA aptamer targeting nucleolin of cancer cells, is the first aptamer
to undergo Phase I clinical trials initiated in 2003 with advanced solid tumors and
proved to be safe without serious toxicity [99]. In the Phase 2 study [135], 44
patient with relapsed/refractory acute myeloid leukemia provide the safety results
across the groups, 21 to AS1411 10 mg/kg/day plus high-dose cytarabine (HiDAC)
(AS1411–10), 9 to AS1411 40 mg/kg/day plusHiDAC (AS1411–40) and 14 to
HiDAC alone (control). The most common toxicities were hematologic, notably
febrile neutropenia, neutropenia, thrombocytopenia, and infections. Except that
grade 3 hypokalemia was more frequent with AS1411–40. Deaths within 28 days
of treatment were AS1411–10, 1/21; AS1411–40, 1/9; and control, 2/14. Response
rates from 39 patients were AS1411–10, 16% (3/19); AS1411–40, 14% (1/7); and
control, 0% (0/13). Data from the clinical trial present the promising signs of the
combination of AS1411 at 10 or 40 mg/kg/day with HiDACto treat patients with
relapsed/refractory AML. No further clinical trial performed on AS1411, because of
the right transform of AS1411 to the Advanced Cancer Therapeutics and renamed
as ACT-GRO-777 [136].
Rosenberg [104] also showed AS1411’s potential in treating acute myeloid
leukemia in combination with cytarabine with less toxicity and special effects.
Both Sgc-8 aptamers (88-mer) [137–139] and its truncated form scg8c (41-mer)
can be internalized into target cells vis receptor-mediated endocytosis. Scg8c specifically targets protein tyrosine kinase-7, which is highly expressed on the membrane
of T-acute lymphoblastic leukemia (ALL) cells, Scg8c can work as capable vehicles to carry drug and targets biomarker on hematopoietic cells, Huang et al. [140]
conjugate Dox to aptamer Sgc8c-7 to accurately deliver and internalize Dox into
CCRF-CEM cells (a T-ALL cell line).
N0XA-12 is an RNA aptamer, acts as the specific antagonist of CXCL12 which can
disrupt the binding of CXCL12 to CXCR4, decline homing and retention of chronic
lymphoblastic leukemia (CLL) cells in bone marrow, and enhance the chemotherapy
and trigger apoptosis of CLL cells in peripheral blood. In a completed phase 2 clinical study on NOX-A12, 28 patients with relapsed/refractory chronic lymphocytic