title: Nitric oxide enhancement of fludarabine cytotoxicity for B-CLL lymphocytes.
abstract: Fludarabine is active but not curative in the treatment of chronic lymphocytic leukemia (B-CLL). Nitric oxide (NO) supplied from exogenous, NO-donating pro-drugs can also induce apoptosis and death of acute leukemia cells. This study investigated combinations of fludarabine with NO-donating pro-drugs for their cytotoxicity against freshly isolated B-CLL lymphocytes following a 72 h exposure in vitro. The median IC(50)for fludarabine was 2.2 microM (n = 85). The nitric oxide donors DETA-NO, PAPA-NO, and MAHMA-NO were also cytotoxic, and their effects were inversely related to rates of NO release. Neither DETA-NO depleted of NO nor DETA itself was effective, indicating that NO was required for cytotoxicity. Drug interactions were evaluated by a modified combination index method. Synergy was observed in combinations of fludarabine or nelarabine (506U78) with DETA-NO in 52% and 88% of samples, respectively. Interestingly, the combination of fludarabine and DETA-NO was more cytotoxic in B-CLL cells less sensitive to fludarabine. DETA-NO did not enhance the activity of other DNA anti-metabolites, topoisomerase I and II inhibitors, or alkylating agents. Finally, the anti-leukemic activity of fludarabine alone or in combination with DETA-NO was found to correlate with inhibition of cellular RNA synthesis. These results indicate that NO donors could enhance fludarabine therapy for B-CLL.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Adams
authors.forename: M C
authors.initials: MC
authors.lastname: Levesque
authors.forename: J B
authors.initials: JB
authors.lastname: Weinberg
authors.forename: K L
authors.initials: KL
authors.lastname: Smith
authors.forename: J L
authors.initials: JL
authors.lastname: Flowers
authors.forename: J
authors.initials: J
authors.lastname: Moore
authors.forename: O M
authors.initials: OM
authors.lastname: Colvin
authors.forename: R
authors.initials: R
authors.lastname: Silber
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000494:pharmacology*; D014226:Triazenes / Q000494:pharmacology; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: C105351:1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene; D014226:Triazenes; D009569:Nitric Oxide; D014740:Vidarabine; C024352:fludarabine