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Sequential treatment of a resistant chronic lymphocytic leukemia patient with bryostatin 1 followed by 2-chlorodeoxyadenosine: case report.

Abstract
Bryostatin 1 (Bryo-1) has been shown to differentiate chronic lymphocytic leukemia (CLL) cells to the hairy cell leukemia phenotype. The purine analogue 2-chlorodeoxyadenosine (2-CdA) exhibits enhanced activity in patients with hairy cell leukemia compared to those with CLL. Here we present a case report of a patient diagnosed with resistant CLL and treated sequentially with Bryo-1 followed by 2-CdA for three cycles. Molecular and biochemical parameters relative to the sequential treatment with these agents in vivo were comparable to those found in the WSU-CLL cell line in vitro (R. M. Mohammad et al., Clin. Cancer Res., 4: 445-453, 1998; R. M. Mohammad et al., Biol. Chem., 379: 1253-1261, 1998). There was a significant reduction of lymphocyte count from 37.1 x 10(3)/microl before the treatment to 3.4 x 10(3)/microl after treatment, and partial remission was achieved 2 months after the treatment. The percentage of morphologically differentiated lymphocytes was increased from 3% before treatment to 92% with the first cycle of Bryo-1. Similarly, expression of CD22, a marker of differentiation, increased from 38% to 97% and was maintained at a high level for the duration of the treatment. Analysis of the molecular markers of apoptosis in isolated peripheral blood lymphocytes revealed an increase in the Bax:Bcl-2 ratio after treatment with Bryo-1 in cycles 2 and 3, with associated poly(ADP-ribose) polymerase cleavage after Bryo-1 and 2-CdA treatment. The deoxycytidine kinase: cytosolic 5'-nucleotidase activity ratio increased modestly after Bryo-1 treatment, indicating increased sensitivity of the peripheral blood lymphocytes to 2-CdA. In summary, we found that sequential treatment with Bryo-1 and 2-CdA caused a significant reduction in peripheral blood lymphocytes (CLL cells) with simultaneous induction of differentiation and the initiation of the Bax: Bcl-2 apoptotic pathway.
AuthorsI Ahmad, A M Al-Katib, F W Beck, R M Mohammad
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 6 Issue 4 Pg. 1328-32 (Apr 2000) ISSN: 1078-0432 [Print] United States
PMID10778958 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antigens, CD
  • Antigens, Differentiation, B-Lymphocyte
  • BAX protein, human
  • Bryostatins
  • CD22 protein, human
  • Cell Adhesion Molecules
  • Integrin alphaXbeta2
  • Lactones
  • Lectins
  • Macrolides
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Sialic Acid Binding Ig-like Lectin 2
  • bcl-2-Associated X Protein
  • bryostatin 1
  • Cladribine
  • Deoxycytidine Kinase
  • 5'-Nucleotidase
Topics
  • 5'-Nucleotidase (drug effects, metabolism)
  • Aged
  • Antigens, CD (analysis)
  • Antigens, Differentiation, B-Lymphocyte (analysis)
  • Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
  • Blotting, Western
  • Bryostatins
  • Cell Adhesion Molecules
  • Cladribine (administration & dosage)
  • Clinical Trials, Phase I as Topic
  • Deoxycytidine Kinase (drug effects, metabolism)
  • Drug Resistance, Neoplasm
  • Flow Cytometry
  • Humans
  • Integrin alphaXbeta2 (analysis)
  • Lactones (administration & dosage)
  • Lectins
  • Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy)
  • Lymphocytes (cytology, drug effects, immunology)
  • Macrolides
  • Male
  • Proto-Oncogene Proteins (drug effects, metabolism)
  • Proto-Oncogene Proteins c-bcl-2 (drug effects, metabolism)
  • Sialic Acid Binding Ig-like Lectin 2
  • bcl-2-Associated X Protein

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