ToxSci Advance Access published online on March 19, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm059
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Recombinant Rat and Mouse Growth Hormones: Risk Assessment of Carcinogenic Potential in 2-year Bioassays in Rats and Mice
GROWTH HORMONE: 2-YEAR RODENT BIOASSAYS
* Merck Research Laboratories, Department of Safety Assessment, West Point, Pennsylvania 19486, USA
Merck Sharp & Dohme-Chibret Laboratories, Research Center, Department of Safety Assessment, BP134, Route de Marsat, 63203 Riom, France
Merck Research Laboratories, Department of Immunology, West Point, Pennsylvania 19486, USA
1 To whom correspondence should be addressed: Dr. Georgia Farris, Merck Research Laboratories, Merck and Co., WP81-402, Sumneytown Pike, West Point, Pennsylvania 19486, USA phone = 215-652-9314, fax = 215-993-7748, email = georgia_farris{at}merck.com
Received December 20, 2006; revision received March 12, 2007; accepted March 13, 2007
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Abstract |
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Recombinant rat Growth Hormone (rrGH) and recombinant mouse Growth Hormone (rmGH) were developed to evaluate the potential carcinogenicity of each biologically active growth hormone as assessed in the respective species. Biological activities of rrGH and rmGH were demonstrated by showing an increase in body weight gain and serum levels of insulin-like growth factor–1 (IGF-1) in hypophysectomized rats receiving daily subcutaneous injections for 6 days. With the exception of pharmacologically mediated weight gain, rrGH and rmGH had no adverse effects in 5-week oral toxicity studies and no production of anti-recombinantGH antibodies. The high doses selected for the carcinogenicity studies provided systemic exposures of GH up to approximately 10 fold over basal levels. In the 105-week mouse carcinogenicity study, daily subcutaneous injections of rmGH at 0.1, 0.2, or 0.5 mg/kg/day were well tolerated and had no effects on survival or incidence of tumors. In the 106-week rat carcinogenicity study, daily subcutaneous injections of rrGH at 0.2, 0.4, or 0.8 mg/kg/day had a favorable effect on longevity in female rats administered 0.4 or 0.8 mg/kg/day, an increased weight gain in females and males, and no increase in the incidence of tumors. The absence of carcinogenic potential of recombinant GH administered daily for 2-years to rodents was consistent with publications of clinical experience indicating a lack of convincing evidence for an increased risk of cancer in children receiving human recombinant GH replacement therapy.
Key Words: Risk Assessment, Endocrine Toxicology - endocrine; other, Agents - pharmaceuticals.
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