Carcinogenicity Evaluation of Baclofen in TgrasH2 Mice

Baclofen is a γ-aminobutyric acid-B receptor agonist used for control of spastic muscle activity and as a treatment for alcohol abuse. The review of the nonclinical database suggested a data gap for potential carcinogenicity following long-term use. Regulatory requirements for pharmaceutical safety testing of cancer-causing potential have historically included 2-year rodent studies in rats and mice. The availability of transgenic models with greater specificity and sensitivity to carcinogens provides safety testing alternatives that align with the 3Rs. The carcinogenicity of baclofen was evaluated in CB6F1-TgrasH2 transgenic mice following daily oral administration at 45, 90, and 180 mg/kg/d for 26 weeks, preceded by a 2-week drug-conditioning period. There were no treatment-related palpable masses or neoplastic findings, and survival rates were not affected by the baclofen treatment. In conclusion, baclofen was considered as noncarcinogenic in CB6F1-TgrasH2 mice, which is consistent with results previously obtained in a 2-year rat study.

[1]  P. Mann,et al.  A Comparison of Spontaneous Tumors in Tg.rasH2 Mice in 26-week Carcinogenicity Studies Conducted at a Single Test Facility during 2004 to 2012 and 2013 to 2018 , 2018, Toxicologic pathology.

[2]  G. Gessa,et al.  Suppressing Effect of Baclofen on Multiple Alcohol-Related Behaviors in Laboratory Animals , 2018, Front. Psychiatry.

[3]  C. Wood,et al.  Characterizing “Adversity” of Pathology Findings in Nonclinical Toxicity Studies , 2016, Toxicologic pathology.

[4]  Lidiya Stavitskaya,et al.  Improving prediction of carcinogenicity to reduce, refine, and replace the use of experimental animals. , 2015, Journal of the American Association for Laboratory Animal Science : JAALAS.

[5]  R. Elbekai,et al.  The 26-Week Tg.Rash2 Mice Carcinogenicity Studies , 2014, Toxicologic pathology.

[6]  Oliver C. Turner,et al.  Regulatory Forum Commentary* , 2014, Toxicologic pathology.

[7]  P. Snyder,et al.  Interpreting Stress Responses during Routine Toxicity Studies , 2013, Toxicologic pathology.

[8]  R. Elbekai,et al.  Incidence of Spontaneous Non-Neoplastic Lesions in Transgenic CBYB6F1-Tg(HRAS)2Jic Mice , 2013, Toxicologic pathology.

[9]  P. Nambiar,et al.  The rasH2 Mouse Model for Assessing Carcinogenic Potential of Pharmaceuticals , 2013, Toxicologic pathology.

[10]  M. Wenk,et al.  Historical Control Data of Spontaneous Tumors in Transgenic CByB6F1-Tg(HRAS)2Jic (Tg.rasH2) Mice , 2013, International journal of toxicology.

[11]  P. Nambiar,et al.  Spontaneous Tumor Incidence in rasH2 Mice , 2012, Toxicologic pathology.

[12]  G. Tomei,et al.  A Benefit-Risk Assessment of Baclofen in Severe Spinal Spasticity , 2004, Drug safety.

[13]  H. Kandori,et al.  Historical Background Data in CB6F1-Tg-rasH2 Mice and CB6F1-nonTg-rasH2 Mice over a 26-Week Experimental Period , 2003 .

[14]  T. Imai,et al.  Interlaboratory Comparison of Short-Term Carcinogenicity Studies Using CB6F1-rasH2 Transgenic Mice , 2003, Toxicologic pathology.

[15]  C. Alden,et al.  The Tg rasH2 Mouse in Cancer Hazard Identification , 2002, Toxicologic pathology.

[16]  D E Robinson,et al.  Background and Framework for ILSI's Collaborative Evaluation Program on Alternative Models for Carcinogenicity Assessment , 2001, Toxicologic pathology.

[17]  M Takoaka,et al.  CB6F1-rasH2 Mouse: Overview of Available Data , 2001, Toxicologic pathology.

[18]  U. Mohr,et al.  International Classification of Rodent Tumors. The Mouse , 2001, Springer Berlin Heidelberg.

[19]  R. Tennant,et al.  Review Article: Use of Transgenic Animals for Carcinogenicity Testing: Considerations and Implications for Risk Assessment , 2000 .

[20]  R. Tennant,et al.  Use of transgenic animals for carcinogenicity testing: considerations and implications for risk assessment. , 2000, Toxicologic pathology.

[21]  J Wahrendorf,et al.  Guidelines for simple, sensitive significance tests for carcinogenic effects in long-term animal experiments. , 1980, IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans. Supplement.