Difluoromethylornithine in combination with tamoxifen in female rats: 13-week oral toxicity study.
OBJECTIVE
Cancer chemoprevention is the use of pharmacologic or natural agents to inhibit the development of cancer. Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase, the rate-limiting enzyme in the biosynthesis of polyamines. DFMO has demonstrated chemopreventive efficacy in animal models of tumorigenesis. Tamoxifen (TAM) is currently used for treatment of estrogen receptor-positive breast carcinoma and has demonstrated efficacy in chemoprevention of breast cancer in women at high risk for the disease. The administration of tamoxifen with DFMO is being considered for development by the National Cancer Institute as a potential drug regimen for the chemoprevention of breast carcinoma.


METHODS
The toxicity of DFMO in combination with TAM was evaluated in female rats following 13 weeks of daily administration by gavage. Dose groups were vehicle control, DFMO (1000 mg/kg per day), low TAM (0.25 mg/kg per day), high TAM (2.5 mg/kg per day), low combination (1000 + 0.25) and high combination (1000 + 2.5).


RESULTS
No mortalities occurred in the study. Clinical signs of toxicity were limited to dermal lesions consisting of scab formation and abrasions produced by DFMO. Administration of either DFMO or TAM resulted in decreased body weight gains, with coadministration having an additive effect. Serum albumin, total protein, cholesterol and triglyceride levels were decreased in all drug-treated dose groups, although histologic evidence of liver lesions were not seen. TAM resulted in increased numbers of red blood cells, whereas DFMO produced a slightly anemic response. DFMO produced lesions in the small intestine consisting of necrosis of crypt epithelium and crypt microabscess, which were enhanced by TAM coadministration. Administration of TAM resulted in histologic changes in the ovaries, fallopian tube, vagina, cervix and uterus, indicating that inhibition of ovulation and reproductive cycle arrest in the proestrus stage had occurred. Coadministration with DFMO did not affect the changes to the reproductive system induced by TAM.


CONCLUSIONS
Coadministration of DFMO with tamoxifen did not result in toxicity unique to the combination drug regimen, but rather toxicity resulted from administration of each drug. Under the conditions of the study, the overall toxicity produced by dual administration of DFMO with tamoxifen was additive with respect to the toxicity associated with each agent alone.
Brown
A P
AP
Toxicology Research Laboratory, Department of Pharmacology, University of Illinois at Chicago (UIC), 1940 West Taylor Street, Chicago, IL 60612-7353, USA. apbrown@uic.edu
Morrissey
R L
RL
Crowell
J A
JA
Levine
B S
BS
D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000633:toxicity*; D001798:Blood Proteins / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000518:Eflornithine / Q000008:administration & dosage / Q000633:toxicity*; D004906:Erythrocyte Count / Q000187:drug effects; D005260:Female; D005836:Genitalia, Female / Q000187:drug effects / Q000473:pathology; D006400:Hematocrit; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D007583:Jejunum / Q000187:drug effects / Q000473:pathology; D051381:Rats; D012709:Serum Albumin / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000473:pathology; D013629:Tamoxifen / Q000008:administration & dosage / Q000633:toxicity*; D013997:Time Factors; D014280:Triglycerides / Q000097:blood; D015430:Weight Gain / Q000187:drug effects
D016588:Anticarcinogenic Agents; D001798:Blood Proteins; D012709:Serum Albumin; D014280:Triglycerides; D013629:Tamoxifen; D002784:Cholesterol; D000410:Alanine Transaminase; D000518:Eflornithine