[In vitro induction of apoptosis in chronic lymphoid leukemia B lymphocytes by theophylline: therapeutic applications].
In a case of indolent stage A chronic lymphocytic leukemia (C.L.L.), treated for ten years only by theophylline for bronchial asthma, we observed spontaneous apoptosis of B lymphocytes (10%). As suggested by these case report, we described new properties of methylxanthine derivatives. In vitro, theophylline increased spontaneous apoptosis after 72 hours in culture of 6 patients by a mean percentage of 80-90% in B-C.L.L. blood lymphocytes (control 20%). Dose-dependent apoptosis involves cyclic nucleotides (AMPc). Using identical theophylline doses, we did not observe apoptosis of normal peripheral blood B lymphocytes. According to French ethical rules, we treated 8 patients with the same doses of theophylline than for bronchial asthma without responses. On the other hand, in 12 aggressive forms of C.L.L., resistant or in relapsed after alkylating agents, methylxanthine derivatives appeared a powerful adjuvant of chlorambucil treatment. We observed 11 responses with less dose of alkylating agents than in previous treatment: decrease in the concentration of blood lymphocytes (11 patients) and clinical remissions (8 patients). Mechanism of action and future of this new drugs combination in the treatment of C.L.L. are discussed.
Binet
J L
JL
Département d'Hématologie, Unité Claude Bernard C20, Groupe d'Hémato-Immunologie Moléculaire URA CNRS-625, Hôpital Pitié-Salpêtrière, Paris.
Mentz
F
F
Baudet
S
S
Ouaaz
F
F
Merle-Béral
H
H
D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects*; D001249:Asthma / Q000188:drug therapy; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D002699:Chlorambucil / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008297:Male; D010431:Pentoxifylline / Q000008:administration & dosage / Q000494:pharmacology*; D012074:Remission Induction; D013806:Theophylline / Q000008:administration & dosage* / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology
D018906:Antineoplastic Agents, Alkylating; D001993:Bronchodilator Agents; D014665:Vasodilator Agents; D002699:Chlorambucil; D013806:Theophylline; D010431:Pentoxifylline
Induction de l'apoptose in vitro des lymphocytes B de la leucémie lymphoïde chronique par la théophylline: applications thérapeutiques.