PT  - JOURNAL ARTICLE
AU  - L. Harivardhan Reddy
AU  - Pierre-Emmanuel Marque
AU  - Catherine Dubernet
AU  - Sinda-Lepêtre Mouelhi
AU  - Didier Desmaële
AU  - Patrick Couvreur
TI  - Preclinical Toxicology (Subacute and Acute) and Efficacy of a New Squalenoyl Gemcitabine Anticancer Nanomedicine
AID  - 10.1124/jpet.107.133751
DP  - 2008 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 484--490
VI  - 325
IP  - 2
4099  - http://jpet.aspetjournals.org/content/325/2/484.short
4100  - http://jpet.aspetjournals.org/content/325/2/484.full
SO  - J Pharmacol Exp Ther2008 May 01; 325
AB  - This study investigates 1) the anticancer efficacy of a new squalenoyl prodrug of gemcitabine (SQgem) in nanoassembly form compared with gemcitabine at equitoxic doses and 2) the subacute and acute preclinical toxicity of these compounds. The toxicity studies revealed that SQgem nanoassemblies, like gemcitabine, were toxic, and they led to dose-dependent mortality after daily i.v. injections for 1 week, irrespective of the route of administration. However, a 4- to 5-day spaced dosing schedule (injections on day 0, 4, 8, and 13) was proved to be safer in terms of weight loss and hematological and other toxicity. Using this spaced dosing schedule, SQgem nanoassemblies exhibited impressive anticancer activity in mice bearing L1210 leukemia because this treatment led to 75% long-term survivors. In contrast, at equitoxic doses, neither free gemcitabine nor cytarabine led to longterm survivors and all the mice of these groups died of the disease. Further toxicity studies performed at lethal doses by blood and serum analysis and organ weight determinations revealed that the hematological toxicity was the dose-limiting toxicity in both SQgem nanoassemblies and gemcitabine, whereas probable gastrointestinal toxicity was also associated with free gemcitabine. The SQgem nanoassemblies did not display hepatotoxicity, which is one of the clinically encountered toxicities of gemcitabine. To summarize, these preclinical studies demonstrated that the toxicological profile of new squalenoyl gemcitabine nanomedicine was not distinct from that of the parent gemcitabine, whereas it was much more potent than gemcitabine at equitoxic doses and cytarabine at clinically relevant doses. These data support the candidature of SQgem for clinical trials. The American Society for Pharmacology and Experimental Therapeutics