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Targeting Cyclooxygenase-2 Reduces Overt Toxicity toward Low-Dose Vinblastine and Extends Survival of Juvenile Mice with Friend Disease

Departments of ¹ Medical Biophysics and ² Molecular and Cellular Biology, Sunnybrook and Women's College Health Sciences Centre and Toronto Sunnybrook Regional Cancer Centre, University of Toronto; ³ Divisions of Haematology/Oncology and Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada; ⁴ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; and ⁵ Ipsogen, Marseille, France

Requests for reprints: Yaacov Ben-David, Division of Molecular and Cellular Biology, Sunnybrook and Women's College Health Sciences Centre, Research Building (S-216), Toronto, Ontario, Canada M4N 3M5. Phone: 416-480-6100; E-mail: bendavid{at}srcl.sunnybrook.utoronto.ca.

Purpose: To test the efficacy of selective therapy against cyclooxygenase-2 in combination with a low-dose regimen of a cytotoxic agent in the treatment of juvenile hematopoietic malignancies in the experimental model, Friend disease.

Experimental Design: Juvenile erythroleukemic mice (n = 8) received no treatment, celecoxib (1600 mg/kg/d), vinblastine (0.5 µg/g twice weekly), vehicle controls, or celecoxib + vinblastine combination (n = 9) over a 6-month period from time of tumor induction. Overt toxicity was assessed daily and recorded weekly.

Results: Among randomly selected mice from celecoxib treatment groups, plasma concentrations ranged from 2 to 6 µmol/L. As a single agent, celecoxib was not associated with any apparent toxicity. Monotherapy with vinblastine, however, caused early mortality marked by severe diarrhea, lethargy, and weight loss. At the tested doses, neither vinblastine nor celecoxib enhanced survival as monotherapies. Coadministration of these two drugs alleviated the overt toxicity associated with vinblastine and resulted in a significant increase in survival (P < 0.05). Survivors sampled throughout the study showed a trend to decreased weight loss and hematocrit levels among all groups, but significance was evidenced earlier in the vinblastine monotherapy group overall (P < 0.05). Despite similar degree of splenomegaly, histologic analysis revealed preserved splenic mantle architecture from mice given combination therapy compared with those sampled from mice on all other monotherapies, exhibiting a more diffuse burden of blasts and destruction of germinal centers.

Conclusion: We propose that addition of a selective cyclooxygenase-2 inhibitor to a modified low-dose conventional chemotherapeutic regimen protects juvenile mice with Friend disease from succumbing to low-dose cytotoxicity, in part, by neutralizing acute inflammatory responses.

Key Words: celecoxib • combination therapy • erythroleukemia

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