Targeting cyclooxygenase-2 reduces overt toxicity toward low-dose vinblastine and extends survival of juvenile mice with Friend disease.
OBJECTIVE
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.


METHODS
Juvenile erythroleukemic mice (n = 8) received no treatment, celecoxib (1600 mg/kg/d), vinblastine (0.5 microg/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 micromol/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.


CONCLUSIONS
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.
Cervi
Dave
D
Department of Medical Biophysics, Sunnybrook and Women's College Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada M4N 3M5.
Klement
Giannoula
G
Stempak
Diana
D
Baruchel
Sylvain
S
Koki
Alane
A
Ben-David
Yaacov
Y
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000139:chemically induced; D000068579:Celecoxib; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005622:Friend murine leukemia virus / Q000235:genetics; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry* / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D015996:Survival Rate; D016896:Treatment Outcome; D014747:Vinblastine / Q000627:therapeutic use*
D000972:Antineoplastic Agents, Phytogenic; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D014747:Vinblastine; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib