title: R-etodolac (SDX-101) and the related indole-pyran analogues SDX-308 and SDX-309 potentiate the antileukemic activity of standard cytotoxic agents in primary chronic lymphocytic leukaemia cells.
abstract: OBJECTIVE
  SDX-101 is the non-cyclooxygenase 2-inhibiting R-enantiomer of the non-steroid anti-inflammatory drug etodolac, and has anti-tumour activity in chronic lymphocytic leukaemia (CLL). SDX-308 and SDX-309 are more potent, structurally related indole-pyran analogues of SDX-101. The current study was performed to investigate and quantify the cytotoxic potentiating effects resulting from a combination of either SDX-101, SDX-308 or SDX-309 with standard cytotoxic agents used in the CLL treatment today.
  
  
  METHODS
  The lymphoma cell line U937-gtb was used, together with primary tumour cells isolated from seven CLL patients. Combinations between chlorambucil and each one of the agents etodolac, SDX-101, SDX-308 and SDX-309 were studied. In addition, SDX-309 was combined with fludarabine, doxorubicin or vincristine. Both simultaneous and sequential exposures were explored using the median-effect method.
  
  
  RESULTS
  Most combinations were additive, which could be of clinical benefit since SDX-101 has been shown to be well tolerated. At the 70% effect level, synergy was observed between SDX-308 and chlorambucil in U937-gtb cells and in two-third of the CLL samples. Since chlorambucil is the most important drug in CLL therapy today and SDX-308 is presently targeted as the lead clinical candidate, this combination would be interesting for further studies. Vincristine and SDX-309 were synergistic in two-fourth of CLL samples.
  
  
  CONCLUSIONS
  To conclude, the non-COX-inhibiting etodolac-derivatives SDX-101, SDX-308 and SDX-309 are potential candidates for combination treatment of CLL. Especially, SDX-308 in combination with chlorambucil warrants further evaluation.
authors.affiliation: Division of Clinical Pharmacology, Uppsala University, Uppsala, Sweden. elin.lindhagen@medsci.uu.se
authors.forename: Elin
authors.initials: E
authors.lastname: Lindhagen
authors.forename: Sara
authors.initials: S
authors.lastname: Nissle
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Leoni
authors.forename: Gary
authors.initials: G
authors.lastname: Elliott
authors.forename: Qi
authors.initials: Q
authors.lastname: Chao
authors.forename: Rolf
authors.initials: R
authors.lastname: Larsson
authors.forename: Anna
authors.initials: A
authors.lastname: Aleskog
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002699:Chlorambucil / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D004357:Drug Synergism; D017308:Etodolac / Q000494:pharmacology*; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008223:Lymphoma / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; C518129:SDX 308; C522289:SDX 309; D002699:Chlorambucil; D017308:Etodolac; D014750:Vincristine; D004317:Doxorubicin