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.
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.
Lindhagen
Elin
E
Division of Clinical Pharmacology, Uppsala University, Uppsala, Sweden. elin.lindhagen@medsci.uu.se
Nissle
Sara
S
Leoni
Lorenzo
L
Elliott
Gary
G
Chao
Qi
Q
Larsson
Rolf
R
Aleskog
Anna
A
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
D006575:Heterocyclic Compounds, 3-Ring; C518129:SDX 308; C522289:SDX 309; D002699:Chlorambucil; D017308:Etodolac; D014750:Vincristine; D004317:Doxorubicin