RESUMO
BACKGROUND: Temsirolimus, a selective inhibitor of the mammalian target of rapamycin, has demonstrated clinical benefit versus investigator's choice (INV) of therapy in patients with relapsed/refractory mantle cell lymphoma (MCL). METHODS: This post hoc study retrospectively assigned simplified Mantle Cell Lymphoma International Prognostic Index (MIPI) scores (ie, secondary MIPI) based on parameters at the time of randomization in patients with MCL (N = 162) who received temsirolimus 175 mg once weekly for 3 weeks followed by once-weekly 75 mg or 25 mg or the INV of active therapy. Outcomes were analyzed according to the low-, intermediate- or high-risk category. RESULTS: Patient distribution by MIPI risk category was 31%, 39%, and 30% in the low-, intermediate-, and high-risk groups, respectively. Among patients in all categories, objective response rate (complete response + partial response) was higher in patients in the temsirolimus 175/75-mg group versus the INV group, respectively: 42% versus 0% (low-risk); 33% versus 5% (intermediate-risk); 10% versus 0% (high-risk). Median progression-free survival was significantly longer with temsirolimus 175/75 mg versus INV, respectively, in patients with intermediate (4.3 vs 1.9 months; P = 0.035) or high (4.5 vs 1.6 months; P = 0.0025) risk, and a trend toward improvement was observed in patients with low risk (5.3 vs 2.6 months; P = 0.091). Improvement in median overall survival was observed with temsirolimus 175/75 mg versus INV in low-risk patients (18.0 vs 10.5 months, respectively; P = 0.069). CONCLUSIONS: This analysis suggests that, compared with INV, temsirolimus demonstrated benefit in all MIPI risk categories in patients with MCL. In all treatment groups, patients with high secondary MIPI scores at baseline faced a dismal prognosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00117598.
RESUMO
Delivery of macromolecular drugs to airway cells after inhalation can be limited by rapid clearance, in vivo degradation, and poor intracellular targeting. Liposome carriers offer an effective method of improving drug stability, but conventional liposomes have limited intracellular targeting capacity and are cleared rapidly by the lungs. Further modification is required to improve liposome-cell interaction and intracellular targeting. Therefore, we proposed conjugating three arginine-rich membrane translocating peptides, namely, HIV-TAT, Antennapedia, and octaarginine, to neutral liposomes as a biocompatible alternative to cationic lipids for intracellular delivery of macromolecules to airway cells. Conjugation did not significantly affect liposome stability, and each system was nebulized to produce aerosols of mean aerodynamic diameter < 1.5 microm. The peptides caused a significant (p < 0.05) increase in liposome-airway cell association compared to untagged liposomes and to DOTAP liposomes. Up to 30% of the peptide-conjugated liposomes added were bound and internalized (via a temperature-dependent, endocytic process) after just 2 h. The novel carriers all delivered encapsulated dextrans rapidly and efficiently to the cytoplasm of Calu-3 cells. Once internalized by the cells, the modified carriers localize for the most part in the cytoplasm with only a small amount of nuclear localization. These peptide-conjugated liposomes were significantly (p < 0.05) less toxic than DOTAP liposomes with octaarginine-coated liposomes the least toxic. These systems, particularly octaarginine-coated liposomes, offer many advantages for drug delivery to airway epithelial cells including increased stability, improved cell binding, and cell uptake with an improved toxicity profile.
