Evaluation of D-methionine as a cytoprotectant in cisplatin treatment of an animal model for ovarian cancer.
BACKGROUND
To evaluate the use of D-methionine(D-met) as a cytoprotectant in the context of clinically relevant doses of cisplatin.


METHODS
Forty five Fischer rats were injected intraperitoneally with 10(6) NuTu-19 cells and treated as follows: group 1 was the control group and received no treatment, group 2 received cisplatin 4 mg/kg and group 3 received cisplatin 4 mg/kg plus D-met. There were two groups that received high dose cisplatin. Group 4 received cisplatin 8 mg/kg and group 5 received cisplatin 8 mg/kg plus D-met. Treatment was initiated four weeks after injection of the NuTu-19 cells, and consisted of four weekly intraperitoneal injections. Serum BUN and creatinine levels in the high dose groups evaluated nephrotoxicity and clinical outcome was measured by mean survival using Kaplan Meier analysis.


RESULTS
There were no significant elevations in serum BUN or creatinine levels in any of the rats treated with high dose cisplatin. In the animals given cisplatin 8 mg/kg plus D-met, death from toxicity was prevented and all animals completed four treatments. In contrast, only two animals in group 4 (cisplatin 8 mg/kg alone) completed 4 treatments. There was a significant improvement in survival for the animals given D-met. (p = .0001) In all treated groups except for group 4, there was an improvement in survival compared to the control group. When comparing groups 2 and 3 (4 mg/kg +/- D-met), there was a subjective decrease in tumor response for group 3 but mean survival was not statistically different. (91 vs. 81 days; p = 0.07) A comparison of groups 2 and 5 revealed no survival benefit using high dose cisplatin with D-met. (91 vs. 79 days; p = 0.10).


CONCLUSIONS
Our results indicate that D-methionine provides cytoprotection against cisplatin toxicity without significant compromise of antitumor activity. All though D-methionine allowed for significant dose intensification of cisplatin above standard doses, there was no survival advantage noted in this group of animals. The indications for its use in the treatment of ovarian cancer remain to be determined.
Cloven
N G
NG
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of California Irvine, Clinical Cancer Center, Building 23, Room 107, Orange CA 92868, USA.
Re
A
A
McHale
M T
MT
Burger
R A
RA
DiSaia
P J
PJ
Rose
G S
GS
Campbell
K C
KC
Fan
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001806:Blood Urea Nitrogen; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D008715:Methionine / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy; D051381:Rats; D011916:Rats, Inbred F344
D000970:Antineoplastic Agents; D008715:Methionine; D003404:Creatinine; D002945:Cisplatin