Phase I pharmacologic study of a new Vinca alkaloid: Navelbine

Mathé, G; Reizenstein, Peter

doi:10.1016/0304-3835(85)90186-7

Cited by 74 publications

(32 citation statements)

References 5 publications

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“…Vinorelbine (5Ј nor-anhydro-vinblastine) is a clinically approved drug that is frequently used in the treatment of various cancers, including metastatic breast cancer (Weber et al, 1995) and nonsmall-cell lung cancer (Gridelli and De Vivo, 2002). Vinorelbine is better tolerated than many of the other vinca alkaloids, including reduced neurotoxicity (Mathé and Reizenstein, 1985) due to its reduced affinity for axonal microtubules (Binet et al, 1990). Liposome-based delivery may further improve the therapeutic index for vinorelbine through an improved pharmacokinetic profile and specific delivery to solid tumors, similar to that observed for liposomal doxorubicin.…”

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confidence: 99%

Improved Pharmacokinetics and Efficacy of a Highly Stable Nanoliposomal Vinorelbine

Drummond¹,

Noble²,

Guo³

et al. 2008

J Pharmacol Exp Ther

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Effective liposomal formulations of vinorelbine (5Ј nor-anhydrovinblastine; VRL) have been elusive due to vinorelbine's hydrophobic structure and resulting difficulty in stabilizing the drug inside the nanocarrier. Triethylammonium salts of several polyanionic trapping agents were used initially to prepare minimally pegylated nanoliposomal vinorelbine formulations with a wide range of drug release rates. Sulfate, poly(phosphate), and sucrose octasulfate were used to stabilize vinorelbine intraliposomally while in circulation, with varying degrees of effectiveness. The release rate of vinorelbine from the liposomal carrier was affected by both the chemical nature of the trapping agent and the resulting drug-to-lipid ratio, with liposomes prepared using sucrose octasulfate displaying the longest half-life in circulation (9.4 h) and in vivo retention in the nanoparticle (t 1/2 ϭ 27.2 h). Efficacy was considerably improved in both a human colon carcinoma (HT-29) and a murine (C-26) colon carcinoma model when vinorelbine was stably encapsulated in liposomes using triethylammonium sucrose octasulfate. Early difficulties in preparing highly pegylated formulations were later overcome by substituting a neutral distearoylglycerol anchor for the more commonly used anionic distearoylphosphatidylethanolamine anchor. The new pegylated nanoliposomal vinorelbine displayed high encapsulation efficiency and in vivo drug retention, and it was highly active against human breast and lung tumor xenografts. Acute toxicity of the drug in immunocompetent mice slightly decreased upon encapsulation in liposomes, with a maximum tolerated dose of 17.5 mg VRL/kg for free vinorelbine and 23.8 mg VRL/kg for nanoliposomal vinorelbine. Our results demonstrate that a highly active, stable, and long-circulating liposomal vinorelbine can be prepared and warrants further study in the treatment of cancer.Nanoparticles such as small unilamellar liposomes have been shown to improve the pharmacokinetics and tumor localization of encapsulated drugs, modify the toxicities associated with a particular drug, and ultimately enhance antitumor efficacy compared with the nonencapsulated drug (Drummond et al., 2008). For the success of liposomal drug delivery, the stable encapsulation of an amphipathic drug in the lumen (Mayer et al., 1985;Haran et al., 1993;Webb et al., 1995;Drummond et al., 2008) of liposomes with long-circulating properties (Allen et al., 2006;Drummond et al., 2008) is preferred, resulting in the ability of such liposomes to localize preferentially in solid tumors through the enhanced permeability and retention effect (Matsumura and Maeda, 1986;Drummond et al., 1999). A liposomal drug is in effect a prodrug, inactive until released from the confines of its carrier, rendering it bioavailable and capable of subsequently acting on its molecular target. Therefore, the ability of the carrier to deliver the active chemical agent to the site of disease, and to subsequently release the drug so as to achieve the desired therapeutic outcome, ar...

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confidence: 99%

Improved Pharmacokinetics and Efficacy of a Highly Stable Nanoliposomal Vinorelbine

Drummond¹,

Noble²,

Guo³

et al. 2008

J Pharmacol Exp Ther

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“…dose level of 35 mg/m 2 was subsequently used in the phase II part of the study. The initial phase I study explored weekly administration of vinorelbine [7] and proposed 30 mg/m 2 for subsequent phase II trials. Administration of the day 15 dose of vinorelbine was however often omitted in following phase II trials due to transient neutropenia and as a consequence we explored a three-weekly schedule administering the drug on days 1 and 8.…”

Section: Discussionmentioning

confidence: 99%

Vinorelbine as first-line or second-line therapy for advanced breast cancer: A Phase I-II trial by the Danish Breast Cancer Co-operative Group

et al. 2008

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“…administration of the drug. Initial phase I studies of vinorelbine were performed in France, and the dose-limiting toxicity was leucopenia -at a dose of 27.5 mg m -2 per week this was seen at grade 3 in 14% of cycles (Mathe and Reizenstein, 1985). In addition, some peripheral neuropathy was noted.…”

Section: Clinical Pharmacologymentioning

confidence: 99%