Sequential treatment of a resistant chronic lymphocytic leukemia patient with bryostatin 1 followed by 2-chlorodeoxyadenosine: case report.
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.
Ahmad
I
I
Department of Medicine, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Al-Katib
A M
AM
Beck
F W
FW
Mohammad
R M
RM
D015720:5'-Nucleotidase / Q000187:drug effects / Q000378:metabolism; D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D000944:Antigens, Differentiation, B-Lymphocyte / Q000032:analysis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015153:Blotting, Western; D054713:Bryostatins; D015815:Cell Adhesion Molecules; D017338:Cladribine / Q000008:administration & dosage; D017321:Clinical Trials, Phase I as Topic; D003842:Deoxycytidine Kinase / Q000187:drug effects / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D006801:Humans; D016167:Integrin alphaXbeta2 / Q000032:analysis; D007783:Lactones / Q000008:administration & dosage; D037102:Lectins; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018942:Macrolides; D008297:Male; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D051918:Sialic Acid Binding Ig-like Lectin 2; D051028:bcl-2-Associated X Protein
D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; C494826:BAX protein, human; D054713:Bryostatins; C497867:CD22 protein, human; D015815:Cell Adhesion Molecules; D016167:Integrin alphaXbeta2; D007783:Lactones; D037102:Lectins; D018942:Macrolides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051918:Sialic Acid Binding Ig-like Lectin 2; D051028:bcl-2-Associated X Protein; C046785:bryostatin 1; D017338:Cladribine; D003842:Deoxycytidine Kinase; D015720:5'-Nucleotidase