Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methotrexate, daunomycin, and chlorambucil were independently conjugated to immune goat gamma-globulins specifically raised to the Ph1 + chronic myelogenous leukemia cell line K-562. The drug-antibody conjugates were then tested against myelosarcomas made up of K-562 cells growing in nude mice and their efficacy was compared with that of the drug alone, gamma-globulins, a mixture of the two, or conjugates of drugs with normal goat gamma-globulin. Conjugation methods for methotrexate and daunomycin abrogate the antibody activity as indicated by the absence of complement-mediated cytotoxicity of the conjugates in vitro and the lack of effect on myelosarcomas in vivo. Simultaneous administration of either of these drugs and antibody partially abrogated the development of myelosarcomas. Chlorambucil-antibody conjugates, however, retained their cytotoxicity in vitro and were found effective in vivo. It is the first successful attempt to covalently bind chlorambucil to gamma-globulins without the loss of drug or antibody biological activity. Although the simultaneous administration of chlorambucil and gamma-globulins and conjugated drug gamma-globulins reduced the growth of myelosarcomas considerably, the immune gamma-globulins alone either reduced their weight to a larger degree or eliminated their growth completely. Results of this study indicate that myelosarcomas made up of K-562 cells grown in nude mice are good and reproducible models for testing various therapeutic agents. The advantage of using human cells proliferating in an in vivo environment brings experimental therapy one step closer to clinical trials.
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PMID:Evaluation of drug-antibody conjugates in the treatment of human myelosarcomas transplanted in nude mice. 692 97

Chronic myeloid leukemia (CML) is characterized by the presence of a constitutively active Abl kinase, which is the product of a chimeric BCR-ABL gene, caused by the genetic translocation known as the Philadelphia chromosome. Imatinib, a selective inhibitor of the Bcr-Abl tyrosine kinase, has significantly improved the clinical outcome of patients with CML. However, subsets of patients lose their response to treatment through the emergence of imatinib-resistant cells, and imatinib treatment is less durable for patients with late stage CML. Although alternative Bcr-Abl tyrosine kinase inhibitors have been developed to overcome drug resistance, a cocktail therapy of different kinase inhibitors and additional chemotherapeutics may be needed for complete remission of CML in some cases. Chlorambucil has been used for treatment of B cell chronic lymphocytic leukemia, non-Hodgkin's and Hodgkin's disease. Here we report that a DNA sequence-specific pyrrole-imidazole polyamide-chlorambucil conjugate, 1R-Chl, causes growth arrest of cells harboring both unmutated BCR-ABL and three imatinib resistant strains. 1R-Chl also displays selective toxicities against activated lymphocytes and a high dose tolerance in a murine model.
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PMID:Growth arrest of BCR-ABL positive cells with a sequence-specific polyamide-chlorambucil conjugate. 1897 32