Related Experiment Video

Updated: Aug 9, 2026

The Lambda Select cII Mutation Detection System
07:08

The Lambda Select cII Mutation Detection System

Published on: April 26, 2018

Chronic toxicity studies of the potential cancer preventive 2-(difluoromethyl)-dl-ornithine

J A Crowell1, E I Goldenthal, G J Kelloff

  • 1Chemoprevention Branch, National Cancer Institute, Bethesda, Maryland 20892.

Fundamental and Applied Toxicology : Official Journal of the Society of Toxicology
|April 1, 1994
PubMed

Insights

This study investigated the chronic toxicity of 2-(difluoromethyl)-dl-ornithine, a potential chemopreventive agent. High doses in rats and dogs caused adverse effects, but findings support further clinical development at lower doses.

Area of Science:

  • Pharmacology
  • Toxicology
  • Oncology

Background:

  • 2-(difluoromethyl)-dl-ornithine is a synthetic compound that inhibits ornithine decarboxylase, reducing polyamine levels crucial for cell cycle progression.
  • The compound has demonstrated chemopreventive efficacy in preclinical epithelial cancer models and serves as a prototype antiproliferative agent.
  • Chronic toxicity studies are essential to evaluate safety and support clinical development of potential chemopreventive agents.

Purpose of the Study:

  • To characterize the toxicities of 2-(difluoromethyl)-dl-ornithine at high dosages in chronic toxicity studies.
  • To determine a no-effect dose for the compound in rodent and canine models.
  • To support the further clinical development of 2-(difluoromethyl)-dl-ornithine as a chemopreventive agent.

Main Methods:

  • Rats were administered 2-(difluoromethyl)-dl-ornithine by gavage for 52 weeks at dosages of 400, 800, and 1600 mg/kg.
  • Dogs were administered the compound by capsule for 52 weeks at dosages of 50, 100, and 200 mg/kg.
  • Adverse effects and no-effect doses were evaluated in both species.

Main Results:

  • In rats, high dosages led to weight loss, increased platelets, alopecia, skin abrasions, dermatitis, liver necrosis, and gastric inflammation; the no-effect dose was 400 mg/kg.
  • In dogs, dosages caused conjunctivitis, hyperkeratosis, alopecia, and cystic intestinal crypts; a no-effect dose was not determined.
  • Observed toxicities were dose-dependent.

Conclusions:

  • Chronic administration of 2-(difluoromethyl)-dl-ornithine at high doses induces toxicities in rats and dogs.
  • The toxicities observed in these studies may be manageable at lower dosages.
  • Findings support the continued investigation of 2-(difluoromethyl)-dl-ornithine in chemopreventive clinical trials.

More Related Videos

Advanced 3D Liver Models for In vitro Genotoxicity Testing Following Long-Term Nanomaterial Exposure08:25

Advanced 3D Liver Models for In vitro Genotoxicity Testing Following Long-Term Nanomaterial Exposure

Published on: June 5, 2020

Dose Uptake of Platinum- and Ruthenium-based Compound Exposure in Zebrafish by Inductively Coupled Plasma Mass Spectrometry with Broader Applications08:46

Dose Uptake of Platinum- and Ruthenium-based Compound Exposure in Zebrafish by Inductively Coupled Plasma Mass Spectrometry with Broader Applications

Published on: April 21, 2022

Related Concept Videos

Cancer Prevention02:59

Cancer Prevention

Several factors can increase the risk of cancer in an individual. About 50% of cancer cases can be prevented by adopting a healthy lifestyle, regular exercise, eating healthy, and following a modest cancer prevention diet. Epidemiological studies have consistently shown that populations with vegetable and fruit-rich diets have reduced the incidence of cancer. On the other hand, populations who have a diet rich in animal fat, red meat, junk food, or high calories are predisposed to cancer.
Some...
Mutagenicity and Carcinogenicity01:25

Mutagenicity and Carcinogenicity

Mutagenicity and carcinogenicity refer to the ability of drugs to cause genetic defects and induce cancer, respectively. The International Agency for Research on Cancer (IARC) classifies agents into four groups based on their carcinogenic potential. Group 1 agents are known human carcinogens; group 2A agents are probably carcinogenic to humans; group 3 agents lack data to support their role in carcinogenesis; and group 4 includes agents for which data support that they are not likely to be...
Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase01:11

Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase

Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
Toxicity Testing in Animals01:23

Toxicity Testing in Animals

Toxicity tests in animals are grounded on two main assumptions: first, the effects observed in laboratory animals can be extrapolated to humans, especially when adjusted for body surface area; second, high-dose exposure in animals is essential to identify potential human hazards from lower doses. This is based on the quantal dose-response concept, which faces the challenge of extrapolating results from relatively few test animals to much larger human populations. For example, a 0.01% incidence...