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Chemosensitivity of lymphocytes from patients with B-cell chronic
lymphocytic leukemia to chlorambucil, fludarabine, and camptothecin analogs
R Silber, B Degar, D Costin, EW Newcomb, M Mani, CR Rosenberg, L Morse, JC Drygas, ZN Canellakis and M Potmesil
Department of Medicine, New York University School of Medicine, New York.
Chemosensitivity of B lymphocytes, obtained from 65 patients with B- cell
chronic lymphocytic leukemia (B-CLL), Rai stages 0 through IV, was
determined using the MTT assay. The results were expressed by the drug
concentration required for 50% inhibition of cell viability (IC50). The
cytotoxicity of chlorambucil (CLB) was compared with that of fludarabine
and the DNA topoisomerase I inhibitors, camptothecin, 9- aminocamptothecin,
10,11-methylenedioxy-20(S)-camptothecin (10,11-MDC) and
9-amino-10,11-methylenedioxy-20(S)-campthothecin (9-A-10,11-MDC), and
topotecan. Considerable heterogeneity in sensitivity to CLB was observed,
with a median IC50 of 40.5 mumol/L in untreated patients. B- CLL cells from
patients treated with CLB had a significantly higher median IC50 of 86.0
mumol/L (P < .01). Untreated as well as CLB-treated patients were
divided into two subsets. For the purpose of this study, B-CLL lymphocytes
with an IC50 CLB of less than 61.0 mumol/L were designated as "sensitive"
and those with an IC50 CLB of > or = 61.0 mumol/L were designated as
"resistant." After baseline assays, 15 untreated patients received CLB;
after treatment, the IC50 increased in B-CLL lymphocytes from 13 of 15
patients. The response to CLB treatment, determined by its effect on the
absolute lymphocyte count and by the Eastern Cooperative Oncology Group
clinical criteria, was significantly better in patients whose lymphocytes
had an IC50 CLB of less than 61.0 mumol/L before therapy (P < .01).
B-CLL lymphocytes also had a variable degree of sensitivity in vitro to
each of the other drugs. There was significant cross-resistance between CLB
and fludarabine (P < 0.01). Whereas only 29% of CLB-resistant
B-lymphocyte specimens obtained from individual patients were sensitive to
fludarabine in vitro, 52% and 67% of CLB-resistant lymphocyte samples were
sensitive to 10,11-MDC and 9-A-10,11-MDC, respectively. We have previously
reported that p53 gene mutations were associated with aggressive B-CLL and
a poor prognosis. B lymphocytes from seven patients with these mutations
were resistant to CLB, and five of six were resistant to fludarabine.
Lymphocytes from four of seven were resistant to 10,11-MDC, and three of
four were resistant to 9-A-10,11- MDC. This study implies that the MTT
assay may be useful in identifying subsets of CLL patients resistant to
conventional chemotherapy. However, definitive conclusions can not be drawn
in view of the small number of patients studied prospectively. In addition,
these results suggest the potential of camptothecin-based therapy for
patients unresponsive to standard treatment.
Volume 84,
Issue 10,
pp. 3440-3446,
11/15/1994
Copyright © 1994 by The American Society of Hematology
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