Phase I Study of Liposomal Vincristine

Gelmon, Karen A.; Tolcher, A.; Diab, Abdel-Aziz; Bally, Marcel B.; Embree, Leanne; Hudon, Norma; Dedhar, C.; Ayers, D.; Eisen, Andrea; Melosky, B.; Burge, C.; Logan, P M; Mayer, Lawrence D.

doi:10.1200/jco.1999.17.2.697

Cited by 97 publications

(42 citation statements)

References 15 publications

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“…29 ± 31 These findings were subsequently extended and confirmed in Phase I/II clinical trials, which have demonstrated the beneficial effects of liposome encapsulation in regard to improved pharmacokinetics and antitumor activity of liposomal vincristine in humans. 32,33 The improved antitumor efficacy of SALP over free [ S] ODNs is consistent with the increased tumor accumulation and homogeneous distribution of [ S] ODNs within the NG tumors. The broad distribution of SALP/ FITC ± [ S] ODNs within the NG tumor mass was confirmed using LSCM analysis.…”

Section: Discussionmentioning

confidence: 55%

Encapsulation of c-myc antisense oligodeoxynucleotides in lipid particles improves antitumoral efficacy in vivo in a human melanoma line

Leonetti¹,

Biroccio²,

Benassi³

et al. 2001

Cancer Gene Ther

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Section: Discussionmentioning

confidence: 55%

Encapsulation of c-myc antisense oligodeoxynucleotides in lipid particles improves antitumoral efficacy in vivo in a human melanoma line

Leonetti¹,

Biroccio²,

Benassi³

et al. 2001

Cancer Gene Ther

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“…Therefore, total plasma VCR exposure following the administration of VSLI appears to be greater than that of conventional VCR because of the difference in elimination. The liposomal encapsulation of VCR protects the drug from the early phase of rapid elimination that is observed with nonliposomal VCR [15] . Previous studies have demonstrated that increasing VCR retention in liposomal systems improves the therapeutic index by increasing the duration of drug exposure to the tumor tissue [8,10,[16][17][18] .…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic characteristics of vincristine sulfate liposomes in patients with advanced solid tumors

et al. 2012

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Aim: To evaluate the single-and multiple-dose pharmacokinetics of vincristine sulfate liposomes (VSLI) in patients with advanced solid tumors. Methods: In single-dose pharmacokinetic study, 16 patients were administered VSLI (1.5, 2.0, or 2.3 mg·m -2 ) through intravenous infusion. Another 6 patients receiving vincristine sulfate (VCR, 2.0 mg) were taken as the control. In multiple-dose pharmacokinetic study, 12 patients were administered VSLI (1.5 or 1.8 mg·m -2 ) through intravenous infusion weekly for 4 consecutive weeks. The plasma concentration of VSLI was determined using the liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Results: After intravenous infusion of the single dose of VSLI, the plasma concentrations were characterized by bi-exponential decline curves. No statistically significant differences were observed between the main pharmacokinetic parameters in the 3 dose groups. Compared with the patients receiving VCR, the patients treated with VSLI displayed an increase in the area under the plasma concentration vs time curve (AUC), and a decrease in plasma clearance rates. On the 4th cycle in the multiple-dose study, the plasma concentration of VCR in all subjects prior to the weekly administration was below the lower limit of quantification (LLOQ). The calculated pharmacokinetic parameters from the subjects in the multiple-and single-dose (1.5 mg·m -2 ) groups had no significant differences. Although the administration of liposomal VCR may significantly elevate the plasma concentration of VCR, VSLI-associated adverse events were similar to those associated with conventional VCR. Conclusion: VSLI exhibits a lower clearance and a higher AUC compared with conventional VCR. No accumulation was observed in patients exposed to VSLI for 4 consecutive weeks. VSLI was generally tolerated in the subjects. The phase II dose of VSLI may be recommended as 4 doses of 1.5 mg·m -2 for treatment of patients with advanced solid tumors.

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“…Our findings suggest that compounds that regulate the polymerization states of microtubules may be used to enhance transfection efficiency by preventing liposome-DNA complexes from degrading in lysosomes. In addition, microtubule inhibitors such as vincristine, 15,16 and microtubule stabilizers such as taxol, 17 are often used in the treatment of cancer, although the effective concentration of these substances often overlaps their toxic dose range. Since it has been reported that encapsulation of these drugs in liposomes is an effective way to reduce their toxicity, [15][16][17][18] gene delivery using liposomes in the presence of such drugs to treat cancer might be a powerful technique due to the dual effects of gene therapy and chemotherapy.…”

Section: Figure 4 Effects Of Nocodazole and Taxol On The Distributionmentioning

confidence: 99%

Microtubule involvement in the intracellular dynamics for gene transfection mediated by cationic liposomes

2001

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7 To improve the efficiency of the transfection, it is essential to elucidate the mechanism not only as to how exogenous DNA is taken up and transported to the nucleus, but also how DNA degrades, since inhibition of the degradation of exogenous DNA could contribute to the enhancement of transfection efficiency, as well as facilitation of the nuclear translocation. Liposome-DNA complex is taken up by endocytosis, and the internalized DNA is released from endosomes by their acidification. [8][9][10] However, the details of intracellular events during lipofection are still unknown. Although many lines of evidence suggest that microtubules are responsible for the intracellular trafficking of materials internalized by endocytosis, 11,12 no direct observation as to how microtubules are involved in the intracellular dynamics of exogenous liposome-DNA complex has been reported. In the present study, therefore, we undertook simultaneous visualization of lipo- some-DNA complexes and microtubules in living cultured cells, and showed that microtubules are involved in the intracellular transport of the exogenous liposome-DNA complex.In order to investigate the contribution of microtubules to the transport of exogenous DNA and liposomes, we tested the effects of nocodazole and taxol on transfection efficiency in COS-7 cells by luciferase assay. For transfection with luciferase plasmids using cationic lipids, pGL3 (Promega, Madison, WI, USA) were complexed with liposomes consisting of DOPE (dioleoylphosphatidylethanolamine; Avanti Polar Lipids, Alabaster, AL, USA) and HyC-Chol (DOPE:HyC-Chol = 2:3 (mol/mol)) to form liposome-DNA complexes. Liposome-DNA complexes were incubated with the cells for 4 h at 37°C, and then the cells were washed and cultured in DMEM for another 24 h at 37°C, followed by a luciferase assay. When cells were treated with nocodazole, which disrupts microtubules, the efficiency of transfection increased dose-dependently and about doubled at 10 m, as shown in Figure 1a. Taxol, which stabilizes microtubules, also enhanced transfection efficiency in a dose-dependent manner (Figure 1b). The concentrations at which these reagents had effects were within the range of their working concentrations to affect microtubules specifically. Therefore, the results suggest that modification of the polymerization states of microtubules changes the efficiency of gene transfection. To examine the possibility that these reagents increased the ability of cells to interact with exogenous liposome-DNA complexes, cells were incubated with the liposome-DNA complexes containing NBD-PE (N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl )-1,2-dihexadecanoyl-sn-glycero-3-phospho-

show abstract

Phase I Study of Liposomal Vincristine

Abstract: The ability to administer elevated doses of vincristine, as well as indications of efficacy, suggests that ONCO-TCS warrants further clinical investigation in a phase II setting.

Cited by 97 publications

References 15 publications

Encapsulation of c-myc antisense oligodeoxynucleotides in lipid particles improves antitumoral efficacy in vivo in a human melanoma line

Encapsulation of c-myc antisense oligodeoxynucleotides in lipid particles improves antitumoral efficacy in vivo in a human melanoma line

Pharmacokinetic characteristics of vincristine sulfate liposomes in patients with advanced solid tumors

Microtubule involvement in the intracellular dynamics for gene transfection mediated by cationic liposomes

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