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Difluoromethylornithine in combination with tamoxifen in female rats : 13-week oral toxicity study

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 efficac... Full description

Journal Title: Cancer chemotherapy and pharmacology 1999, Vol.44 (6), p.475-483
Main Author: BROWN, A. P
Other Authors: MORRISSEY, R. L , CROWELL, J. A , LEVINE, B. S
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: Berlin: Springer
ID: ISSN: 0344-5704
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recordid: cdi_crossref_primary_10_1007_s002800051121
title: Difluoromethylornithine in combination with tamoxifen in female rats : 13-week oral toxicity study
format: Article
creator:
  • BROWN, A. P
  • MORRISSEY, R. L
  • CROWELL, J. A
  • LEVINE, B. S
subjects:
  • Administration, Oral
  • Alanine Transaminase - blood
  • Animals
  • Anticarcinogenic Agents - administration & dosage
  • Anticarcinogenic Agents - toxicity
  • Biological and medical sciences
  • Blood Proteins - metabolism
  • Bone Marrow Cells - drug effects
  • Bone Marrow Cells - pathology
  • Cholesterol - blood
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Drug toxicity and drugs side effects treatment
  • Eflornithine - administration & dosage
  • Eflornithine - toxicity
  • Erythrocyte Count - drug effects
  • Female
  • Genitalia, Female - drug effects
  • Genitalia, Female - pathology
  • Hematocrit
  • Humans
  • Intestinal Mucosa - drug effects
  • Intestinal Mucosa - pathology
  • Jejunum - drug effects
  • Jejunum - pathology
  • Medical sciences
  • Miscellaneous (drug allergy, mutagens, teratogens...)
  • Pharmacology. Drug treatments
  • Rats
  • Serum Albumin - metabolism
  • Skin - drug effects
  • Skin - pathology
  • Tamoxifen - administration & dosage
  • Tamoxifen - toxicity
  • Time Factors
  • Triglycerides - blood
  • Weight Gain - drug effects
ispartof: Cancer chemotherapy and pharmacology, 1999, Vol.44 (6), p.475-483
description: 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. 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). 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. 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.
language: eng
source:
identifier: ISSN: 0344-5704
fulltext: no_fulltext
issn:
  • 0344-5704
  • 1432-0843
url: Link


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titleDifluoromethylornithine in combination with tamoxifen in female rats : 13-week oral toxicity study
creatorBROWN, A. P ; MORRISSEY, R. L ; CROWELL, J. A ; LEVINE, B. S
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descriptionCancer 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. 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). 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. 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.
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languageeng
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subjectAdministration, Oral ; Alanine Transaminase - blood ; Animals ; Anticarcinogenic Agents - administration & dosage ; Anticarcinogenic Agents - toxicity ; Biological and medical sciences ; Blood Proteins - metabolism ; Bone Marrow Cells - drug effects ; Bone Marrow Cells - pathology ; Cholesterol - blood ; Dose-Response Relationship, Drug ; Drug Interactions ; Drug toxicity and drugs side effects treatment ; Eflornithine - administration & dosage ; Eflornithine - toxicity ; Erythrocyte Count - drug effects ; Female ; Genitalia, Female - drug effects ; Genitalia, Female - pathology ; Hematocrit ; Humans ; Intestinal Mucosa - drug effects ; Intestinal Mucosa - pathology ; Jejunum - drug effects ; Jejunum - pathology ; Medical sciences ; Miscellaneous (drug allergy, mutagens, teratogens...) ; Pharmacology. Drug treatments ; Rats ; Serum Albumin - metabolism ; Skin - drug effects ; Skin - pathology ; Tamoxifen - administration & dosage ; Tamoxifen - toxicity ; Time Factors ; Triglycerides - blood ; Weight Gain - drug effects
ispartofCancer chemotherapy and pharmacology, 1999, Vol.44 (6), p.475-483
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1MORRISSEY, R. L
2CROWELL, J. A
3LEVINE, B. S
title
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1Cancer chemotherapy and pharmacology
addtitleCancer Chemother Pharmacol
descriptionCancer 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. 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). 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. 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.
subject
0Administration, Oral
1Alanine Transaminase - blood
2Animals
3Anticarcinogenic Agents - administration & dosage
4Anticarcinogenic Agents - toxicity
5Biological and medical sciences
6Blood Proteins - metabolism
7Bone Marrow Cells - drug effects
8Bone Marrow Cells - pathology
9Cholesterol - blood
10Dose-Response Relationship, Drug
11Drug Interactions
12Drug toxicity and drugs side effects treatment
13Eflornithine - administration & dosage
14Eflornithine - toxicity
15Erythrocyte Count - drug effects
16Female
17Genitalia, Female - drug effects
18Genitalia, Female - pathology
19Hematocrit
20Humans
21Intestinal Mucosa - drug effects
22Intestinal Mucosa - pathology
23Jejunum - drug effects
24Jejunum - pathology
25Medical sciences
26Miscellaneous (drug allergy, mutagens, teratogens...)
27Pharmacology. Drug treatments
28Rats
29Serum Albumin - metabolism
30Skin - drug effects
31Skin - pathology
32Tamoxifen - administration & dosage
33Tamoxifen - toxicity
34Time Factors
35Triglycerides - blood
36Weight Gain - drug effects
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1MORRISSEY, R. L
2CROWELL, J. A
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titleDifluoromethylornithine in combination with tamoxifen in female rats : 13-week oral toxicity study
authorBROWN, A. P ; MORRISSEY, R. L ; CROWELL, J. A ; LEVINE, B. S
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0Administration, Oral
1Alanine Transaminase - blood
2Animals
3Anticarcinogenic Agents - administration & dosage
4Anticarcinogenic Agents - toxicity
5Biological and medical sciences
6Blood Proteins - metabolism
7Bone Marrow Cells - drug effects
8Bone Marrow Cells - pathology
9Cholesterol - blood
10Dose-Response Relationship, Drug
11Drug Interactions
12Drug toxicity and drugs side effects treatment
13Eflornithine - administration & dosage
14Eflornithine - toxicity
15Erythrocyte Count - drug effects
16Female
17Genitalia, Female - drug effects
18Genitalia, Female - pathology
19Hematocrit
20Humans
21Intestinal Mucosa - drug effects
22Intestinal Mucosa - pathology
23Jejunum - drug effects
24Jejunum - pathology
25Medical sciences
26Miscellaneous (drug allergy, mutagens, teratogens...)
27Pharmacology. Drug treatments
28Rats
29Serum Albumin - metabolism
30Skin - drug effects
31Skin - pathology
32Tamoxifen - administration & dosage
33Tamoxifen - toxicity
34Time Factors
35Triglycerides - blood
36Weight Gain - drug effects
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1MORRISSEY, R. L
2CROWELL, J. A
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pages475-483
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abstractCancer 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. 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). 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. 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.
copBerlin
pubSpringer
pmid10550568
doi10.1007/s002800051121