Temple University

Thomas Jefferson University

Bruno Calabretta

Alan M Gewirtz

Robert V Martinez

Tomasz Skorski

Donatella Venturelli

Oligonucleotides are provided having a nucleotide sequence complementary to at least a portion of the mRNA transcript of the human c-kit gene. These 'antisense' oligonucleotides are hybridizable to the c-kit mRNA transcript. Such oligonucleotides are useful in selectively inhibiting proliferation of erythroid cells, particularly in disorders characterized by an elevated hematocrit due to over-production of erythrocytes. The antisense oligomers also have activity agent hematologic neoplastic cells and are therefore suitable as bone marrow purging agents.

Antisense of oligonucleotides to c-kit proto-oncogene and in vitro

DR-nm23 protein is disclosed. A nucleotide sequence encoding the same and fragments thereof, recombinant expression vectors that comprise the nucleotide sequence, host cell comprising the recombinant expression vectors and methods of making DR-nm23 protein are disclosed. Oligonucleotide molecules comprising a nucleotide sequence complementary to a portion of the nucleotide sequence that encodes DR-nm23 and methods of using the same to inhibit DR-nm23 expression are disclosed. Isolated antibodies that bind to an epitope on DR-nm23 are disclosed. Methods of tracking the progress on chronic myelogenous leukemia and methods of detecting the onset of blast crisis phase in an individual with chronic myelogenous leukemia are disclosed.

DR-nm23 and compositions, methods of making and methods of using the same

Therapeutic combinations of two or more antisense oligonucleotides are provided. At least one first antisense oligonucleotide specific for a cytoplasmic oncogene or proto-oncogene and at least one second antisense oligonucleotide specific for a nuclear oncogene or proto-oncogene are combined for treatment of a neoplastic disease. The first antisense oligonucleotide may be specific for, e.g., a ras or raf gene, or an oncogene which codes for a protein tyrosine kinase. The nuclear gene-targeting antisense oligonucleotide preferably may be specific for a nuclear oncogene or proto-oncogene which encodes a transcriptional factor. The combined oligonucleotides have enhanced activity against neoplastic disease.

Antisense oligonucleotides targeting cooperating oncogenes

Leukemias characterized by the presence of the Philadelphia chromosome and the expression of the hybrid bcr-abl gene are treated with antisense oligonucleotides complementary to a target sequence of the bcr-abl mRNA transcript including the breakpoint junction. Individual chronic myelogoneous leukemia patients or Philadelphia chromosome-positive acute lymphocytic leukemia patients are treated by first sequencing the individual's bcr-abl breakpoint junction, and then administering antisense oligonucleotides complementary thereto. The oligonucleotides are designed to hybridize specifically to the bcr-abl breakpoint junction without substantial cross hybridization to untranslocated c-abl sequences. Treatment may comprise in vivo administration of antisense oligonucleotides, or ex vivo treatment such as bone marrow purging.

Selective inhibition of leukemic cell proliferation by bcr-abl antisense

The effectiveness of selected antineoplastic agents may be determined in individual patients by comparing the level of expression of one or more selected growth-regulated genes in neoplastic cells taken from the patient before and shortly after the initiation of therapy. A decrement in expression is prognostic of eventual remission, while a lack of decrement indicates that remission is unlikely. The test may also be accomplished by comparing the level of expression of growth-regulated genes in neoplastic cells in culture before and after incubation of the cells with the selected antineoplastic agents.

Method for predicting the effectiveness of antineoplastic therapy in

A c-myb transfected cell line capable of producing a selected growth factor is provided. In a preferred embodiment, human glioblastoma cells are co-transfected with a first plasmid containing human c-myb DNA and second plasmid containing the gene encoding hygromycin resistance. Methods of producing selected growth factors employing cell line are also provided.

C-myb transfected T98G cells which produce GM-CSF and stem cell factor

Oligonucleotides are provided having a nucleotide sequence complementary to at least a portion of the mRNA transcript of the human c-myb gene. These 'antisense' oligonucleotides are hybridizable to the c-myb mRNA transcript. Such oligonucleotides are useful in treating hematologic neoplasms and in inducing immunosuppression. They are particularly useful as bone marrow purging agents.

Growing community of inventors

Philadelphia, PA, United States of America

Bruno Calabretta