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)

Cell kinetics were studied in human leukemia (acute leukemia, chronic myelocytic leukemia and other myelocytic malignancies) and in mouse leukemia (L 1210 cells). Flow cytometry method was employed for the analysis of DNA distribution of cells stained with propidium iodide, using a cytofluorograf (System 50, Ortho Instruments). The DNA per cell frequency distribution histograms (DNA histogram) in normal human lymphocytes from peripheral blood showed one main peak of diploid, which corresponded to the DNA from cells in G1 phase of the cell cycle, and other small portions, which corresponded to the DNA from cells in S, G2 and M compartments (S + G2 + M). The percentage of the number of cells in the S + G2 + M phase to the total cells from normal controls was 2.1%. In the case of untreated acute myelocytic leukemia (AML), the percentages of cells in the S + G2 + M phase from peripheral blood and bone marrow were 2.4% and 7.1%, respectively. In bone marrow from treated AML, the percentage of cells in the S + G2 + M phase increased to 14.8%. In the case of untreated acute lymphocytic leukemia, the percentages of the S + G2 + M phase from peripheral blood and bone marrow were 1.9% and 7.1%, respectively. After the treatment of chronic myelocytic leukemia, the percentages of the S + G2 + M phase in peripheral blood and bone marrow were 5.8% and 12.2%, respectively. The DNA histogram in untreated L 1210 cells showed two peaks. One of the peak was consisted of the DNA from cells in G1 phase and another was from cells in the S + G2 + M phase. The proportion of the S + G2 + M phase in the L 1210 cells treated with antitumor drugs significantly increased compared to the untreated cells. The findings indicate that the increase in the proportion of the S + G2 + M phase in the cells from treated human leukemia was a result of the therapeutic effects of antitumor drugs. The study of cell kinetics may provide benefits to know the effect of antitumor drugs during the treatment of human leukemia.
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PMID:[Studies on cell kinetics in leukemia using flow cytometry]. 715 63

Cladribine, an adenosine deaminase inhibitor, has been developed and launched by Ortho Biotech in collaboration with The Scripps Research Institute for the treatment of several neoplasms, including acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneos T-cell lymphoma, hairy-cell leukemia and non-Hodgkin's lymphoma. It was first launched in the US in February 1993. Ortho Biotech and The Scripps Research Institute have since been developing the compound for its potential use in multiple sclerosis (MS). In 1997, Ortho filed air NDA in the US for the use of cladribine in the treatment of relapsing-remitting and secondary progressive MS. An FDA drug advisory committee was planning to meet in January 1999 to discuss the NDA. However, Ortho cancelled the meeting. Following an FDA inspection during December 1998 and January 1999, the Scripps Clinic received a warning letter from the FDA in April 1999 regarding violations in the clinical studies of cladribine for MS, and Ortho withdrew the NDA after concluding that further clinical studies would be necessary. Cladribine has been known since the 1960s as an intermediate for the synthesis of 2-deoxynucleotides and its potential for the treatment of leukemia was disclosed in 1984. The Scripps Research Institute and the Johnson & Johnson group hold several patents claiming preparation methods (US 05208327), and additional indications, such as multiple sclerosis (WO-09316706) and rheumatoid arthritis (US-05310732). The associated patent, WO-09323508, is the only one among those patents that claims the use of unmodified cladribine for the treatment of leukemia, but it focuses particularly on a specific form of the disease, chronic myelogenous leukemia. Analysts at UBS Warburg predicted in October 2001, that the product would make US sales of $50 million in 2004 for its MS indication.
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PMID:Cladribine. Ortho Biotech Inc. 1189 41

The treatment of patients with chronic myeloid leukemia (CML) is evolving rapidly. With conventional chemotherapy the clinical course is characterized by a chronic phase (median duration, 4 to 5 years), followed by an accelerated phase with transition to a terminal blast crisis. Treatment with busulfan or hydroxyurea does not alter the natural history. Interferon alfa (IFN-alpha) prolongs life expectancy by approximately 20 months but is associated with significant toxicity. Evidence indicates that bone marrow transplantation from a related human leukocyte antigen (HLA)-identical donor can be curative in younger patients. However, transplantation is available to only a minority of patients and entails severe toxicity and transplant-related mortality. Dramatic advances in the understanding of the molecular pathophysiology of CML have led to a new era of targeted therapy. The specific tyrosine kinase inhibitor imatinib mesylate demonstrates a high level of efficacy in CML with acceptable toxicity. Farnesyltransferase inhibitors (FTIs) are another important class of targeted agents with the potential to act at multiple sites within dysregulated signal transduction networks. ZARNESTRA (formerly R115777, Ortho Biotech Oncology, Raritan, NJ), an oral FTI, has shown activity and is well tolerated in both chronic- and accelerated-phase patients. With their mechanistic specificity, the new modalities offer the promise of increased antileukemic activity and an improved therapeutic index.
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PMID:Chronic myeloid leukemia: current therapies and the potential role of farnesyltransferase inhibitors. 1221 88

Acute leukemia carries a poor prognosis, especially in older patients, emphasizing the need for novel therapies. Reasons for treatment failure include high rates of relapse and treatment-related toxicities. Farnesyltransferase inhibitors (FTIs), a new class of agents that can interfere with intracellular signaling, are good therapeutic candidates for study in these diseases, given the relatively high levels of the target enzyme, farnesyltransferase, expressed in bone marrow and by peripheral circulating lymphocytes. ZARNESTRA (formerly R115777, Ortho Biotech Oncology, Raritan, NJ) is an FTI that has clinical activity in solid tumors and antileukemic activity in vitro. In a phase I trial of Zarnestra in patients with high-risk leukemia (resistant or relapsed acute myeloid leukemia [AML] or acute lymphocytic leukemia [ALL], chronic myeloid leukemia [CML] in blast crisis, or AML in poor prognosis subgroups), patients experienced an overall response rate of 29%. Zarnestra was well tolerated with no dose-limiting toxicities through doses up to 900 mg twice daily. Assays measuring inhibition of farnesyltransferase activity showed a reliable inhibition at doses greater than 300 mg twice daily, and pharmacokinetic studies indicated that Zarnestra accumulated preferentially in the bone marrow in a dose-dependent fashion. These results suggest that Zarnestra should be studied further in patients with myeloid leukemia.
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PMID:Farnesyltransferase inhibitors and myeloid malignancies: phase I evidence of Zarnestra activity in high-risk leukemias. 1221 91

Imatinib mesylate (IM), a small molecule that is a selective inhibitor of the ABL, platelet derived growth factor receptor (PDGFR-R) and stem cell ligand receptor (c-kit) tyrosine kinases (TK). IM was also found to inhibit the TK activity of BCR/ABL fusion protein produced in chronic myelogenous leukemia, with marked clinical activity against the disease. Since both PDGF-R and c-kit both having a putative role in tumorigenesis, we investigated the efficacy and safety of the use of IM in patients with endocrine tumors unresponsive to conventional therapies that expressed c-kit and/or PDGF-R (within the framework of a comprehensive phase II multi-center study of IM in patients with solid tumors). IM was initiated at a dose of 400 mg/day, with possible dose escalation within 1 week to 600 mg/day and an option to raise the dose to 800 mg/day in the event of progression and in the absence of safety concerns for a period of up to 12 months. Between September 2002 and July 2003, 15 adult patients with disseminated endocrine tumors were recruited as follows: medullary thyroid carcinoma (MTC, n = 6); adrenocortical carcinoma (ACC, n = 4); malignant pheochromocytoma (pheo, n = 2); carcinoid (non-secreting, n = 2), neuroendocrine tumor (NET, n = 1). No objective responses were observed. MTC--disease progression in 4 patients, and treatment discontinuation in 2 patients due to adverse events; ACC--disease progression in 3 patients, and treatment discontinuation in 1 patient due to severe psychiatric adverse event; Pheo--disease progression in 2 patients; Carcinoid--stable disease in 1 patient (6.5 months), and disease progression in 1 patient; NET--disease progression in 1 patient. IM does not appear to be useful for treatment of malignant endocrine tumors, also causing significant toxicity in this patient population.
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PMID:The role of imatinib mesylate (Glivec) for treatment of patients with malignant endocrine tumors positive for c-kit or PDGF-R. 1672 80