Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0023473 (
chronic myeloid leukemia
)
18,916
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
To design a specific immunotherapy for leukemia patients, the identification of leukemia-associated antigens (LAAs) is a pivotal step. Antileukemic effects after hematopoetic stem cell transplantation for myeloid leukemias are observed and might be related to the recognition of LAAs. Using the serological screening of an expression library (SEREX) of K562 cells, we identified 16 different clones encoding LAAs eliciting a humoral immune response, among them the heat shock proteins HSJ2 and HSP70, the
M-phase phosphoprotein 11
(
MPP11
), the BRCA1-associated protein (BRAP), the Jkappa recombination binding protein (RBPJkappa) and the receptor for hyaluronic acid mediated motility (RHAMM). Serological responses to
MPP11
were observed in 7/19 (37%) of patients with acute myeloid leukemia (AML) and 6/16 (38%) of patients with
chronic myeloid leukemia
(
CML
), but not in healthy volunteers (0/20). IgG antibodies directed against
MPP11
were also detected in 25-50% of the sera of patients with solid tumors such as melanoma, renal cell, ovarian and breast carcinoma. mRNA expression of
MPP11
was detected in 20/20 AML patients and 7/10 patients with
CML
. In normal tissues, strong mRNA expression of
MPP11
was only detected in testis. By real-time PCR, we detected upregulation of
MPP11
in leukemic blasts. Simultaneous humoral immune responses to 2 or more of the 16 LAAs identified here was observed, suggesting the feasibility of a polyvalent vaccination as an option for immunotherapies in leukemia patients.
...
PMID:Characterization of several leukemia-associated antigens inducing humoral immune responses in acute and chronic myeloid leukemia. 1280 Jan 98
Blockade of Bcr-Abl by the inhibitor Imatinib has proven efficacious in the therapy of
chronic myelogenous leukemia
(
CML
). However resistance to the drug emerges at the advanced phases of the disease. Therefore, novel therapy models remained to be designed. We have developed a novel dual targeted agent termed "combi-molecule" designed to not only block Bcr-Abl but also damage DNA.
ZRF1
, the first optimized prototype of the approach, was "programmed" to degrade into another inhibitor ZRF0 plus a methyl diazonium species. It was approximately 2-fold stronger Abl tyrosine kinase inhibitor than Imatinib and a more potent DNA-damaging agent than Temodal. In the p53 wild-type Mo7p210 cells, the potency of
ZRF1
was approximately 1,000-fold superior to that of the equieffective combinations of Imatinib plus Temodal. More importantly, its superior potency over Imatinib was more pronounced in Bcr-Abl-positive cells coexpressing wild-type p53. Studies to rationalize these results showed that, through its Bcr-Abl inhibitory function, it down-regulated p53. However, sufficient level of the latter protein was available for transactivating p21 and Bax, which are required for cell cycle arrest and apoptosis. The results suggest that, in p53 wild-type cells, apoptosis is induced not only through Bcr-Abl inhibition but also through the p53-controlled DNA-damaging pathway, leading to an additive effect that translates into enhanced cell death. The study conclusively showed that p53 is a major determinant for the cytotoxic advantages of the novel combi-molecular approach in
CML
, a disease in which 70% to 85% of all the cases express wild-type p53.
...
PMID:Combi-targeting concept: an optimized single-molecule dual-targeting model for the treatment of chronic myelogenous leukemia. 1848 93
