Reddy L Harivardhan, Marque Pierre-Emmanuel, Dubernet Catherine, Mouelhi Sinda-Lepêtre, Desmaële Didier, Couvreur Patrick
Université Paris-Sud XI, Faculté de Pharmacie, Unité Mixte de Recherche Centre National de la Recherche Scientifique 8612, Institut Fédératif de Recherche 141, 92296 Châtenay-Malabry Cedex, France.
J Pharmacol Exp Ther. 2008 May;325(2):484-90. doi: 10.1124/jpet.107.133751. Epub 2008 Feb 7.
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.
1）吉西他滨的一种新型角鲨烯酰前药（SQgem）纳米组装体形式与等毒性剂量的吉西他滨相比的抗癌疗效，以及2）这些化合物的亚急性和急性临床前毒性。毒性研究表明，SQgem纳米组装体与吉西他滨一样具有毒性，每日静脉注射1周后，无论给药途径如何，它们都会导致剂量依赖性死亡。然而，就体重减轻、血液学及其他毒性而言，4至5天的间隔给药方案（第0、4、8和13天注射）被证明更安全。采用这种间隔给药方案，SQgem纳米组装体在携带L1210白血病的小鼠中表现出令人印象深刻的抗癌活性，因为这种治疗导致75%的长期存活者。相比之下，在等毒性剂量下，游离吉西他滨和阿糖胞苷均未产生长期存活者，这些组的所有小鼠均死于该疾病。通过血液和血清分析以及器官重量测定在致死剂量下进行的进一步毒性研究表明，血液学毒性是SQgem纳米组装体和吉西他滨的剂量限制性毒性，而可能的胃肠道毒性也与游离吉西他滨有关。SQgem纳米组装体未表现出肝毒性，而肝毒性是吉西他滨临床上遇到的毒性之一。总之，这些临床前研究表明，新型角鲨烯酰吉西他滨纳米药物的毒理学特征与母体吉西他滨并无明显差异，而在等毒性剂量下它比吉西他滨更有效，在临床相关剂量下比阿糖胞苷更有效。这些数据支持SQgem用于临床试验的候选资格。
