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.
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Authors | I Ahmad, A M Al-Katib, F W Beck, R M Mohammad |
Journal | Clinical 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 |
PMID | 10778958
(Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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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
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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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