[Comparison of platinum-containing doublet chemotherapy and liposome paclitaxel monotherapy for the treatment of elderly patients with advanced non-small cell lung cancer].

OBJECTIVE: Given controversy remains on monotherapy and combinatory chemotherapy in elderly patients (> or = 70 years) with advanced non-small cell lung cancer (NSCLC), we conducted this study to compare the safety and efficacy of liposome paclitaxel and platinum-containing doublets. METHODS: From January 2007 to March 2009, totally 65 patients (age > or = 70 years) with pathologically confirmed NSCLC were enrolled. 33 patients received liposome paclitaxel monotherapy (monotherapy group) and 32 patients received platinum-containing doublets chemotherapy (combinatory group). RESULTS: No CR was observed in all patients. Both groups had similar objective response rate (ORR) (6.1% vs. 15.6%, P = 0.399). However, a statistically significant higher disease control rate (DCR) (65. 6%) was observed in he combinatory group when compared with that of monotherapy group (39.4%, P = 0.034). The combinatory group had longer time-to-progression (TTP) (94 days, 95% CI: 60-127 days) than the monotherapy group (51 days, 95% CI: 22-79 days, P = 0.046). The median overall survival days in the combinatory group was 524 days (95% CI: 146-901 days) where as in the monotherapy group only 146 days (95% CI 32-259 days) (P = 0.001). The most common adverse reactions were myelosuppression, gastrointestinal reactions and elevated transaminase in the monotherapy group, while those were myelosuppression, gastrointestinal reactions and infection in the combinatory group. Generally there was no significant difference in the adverse reaction, except grade 3-4 thrombocytopenia (P = 0.004). It should be addressed that 1 patient (3.0%) in the monotherapy group had an onset of severe infection, while the number rose to 5 (15.6%) in the combinatory group (P = 0.079). CONCLUSION: Platinum-containing doublet chemotherapy achieved a higher response rate, longer time-to-progression and overall survival compared with liposome paclitaxel monotherapy in the treatment of elderly patients with advanced NSCLC. However thrombocytopenia and severe infection should be monitored for the combinatory chemotherapy.

A promising cancer gene therapy agent based on the matrix protein of vesicular stomatitis virus.

The matrix (M) protein of vesicular stomatitis virus (VSV) plays a key role in inducing cell apoptosis during infection. To investigate whether M protein-mediated apoptosis could be used in cancer therapy, its cDNA was amplified and cloned into eukaryotic expression vector pcDNA3.1(+). The recombinant plasmid or the control empty plasmid pcDNA3.1(+) was mixed with cationic liposome and introduced into various tumor cell lines in vitro, including lung cancer cell LLC, A549, colon cancer cell CT26 and fibrosarcoma cell MethA. Our data showed that the M protein induced remarkable apoptosis of cancer cells in vitro compared with controls. Fifty micrograms of plasmid in a complex with 250 microg cationic liposome was injected intratumorally into mice bearing LLC or MethA tumor model every 3 days for 6 times. It was found that the tumors treated with M protein plasmid grew much more slowly, and the survival of the mice was significantly prolonged compared with the mice treated with the control plasmid. In MethA fibrosarcoma, the tumors treated with M protein plasmid were even completely regressed, and the mice acquired longtime protection against the same tumor cell in rechallenge experiments. Both apoptotic cells and CD8(+) T cells were widely distributed in M protein plasmid-treated tumor tissue. Activated cytotoxic T lymphocytes (CTLs) were further detected by means of (51)Cr release assay in the spleen of the treated mice. These results showed that M protein of VSV can act as both apoptosis inducer and immune response initiator, which may account for its extraordinary antitumor effect and warrant its further development in cancer gene therapy.

Vesicular stomatitis virus matrix protein gene enhances the antitumor effects of radiation via induction of apoptosis.

Vesicular stomatitis virus (VSV) matrix (M) protein can directly induce apoptosis by inhibiting host gene expression when it is expressed in the absence of other viral components. Previously, we found that the M protein gene complexed to DOTAP-cholesterol liposome (Lip-MP) can suppress malignant tumor growth in vitro and in vivo; however, little is known regarding the biological effect of Lip-MP combined with radiation. The present study was designed to determine whether Lip-MP could enhance the antitumor activity of radiation. LLC cells treated with a combination of Lip-MP and radiation displayed apparently increased apoptosis compared with those treated with Lip-MP or radiation alone. Mice bearing LLC or Meth A tumors were treated with intratumoral or intravenous injections of Lip-MP and radiation. The combined treatment significantly reduced mean tumor volumes compared with either treatment alone in both tumor models and prolonged the survival time in Meth A tumor models and the intravenous injection group of LLC tumor models. Moreover, the antitumor effects of Lip-MP combined with radiation were greater than their additive effects when compared with the expected effects of the combined treatment in vivo. This study suggests that Lip-MP enhanced the antitumor activity of radiation by increasing the induction of apoptosis.

Antitumour activity of cationic-liposome-conjugated adenovirus containing the CCL19 [chemokine (C-C motif) ligand 19] gene.

CCL19 [chemokine (C-C motif) ligand 19; also known as MIP-3beta (macrophage inflammatory protein-3beta) or ELC (Epstein-Barr-virus-induced molecule 1 ligand chemokine)], one of the immunostimulatory cytokines, chemoattracts both DCs (dendritic cells) and T-lymphocytes. Adenoviral vector is one of the most used gene delivery vectors for cancer therapy because of its high gene-transfection efficiency. However, its wider application is limited, owing to immune responses that reduce transgene expression and decrease the efficacy of repeated administration. We constructed the recombinant replication deficient adenoviral vectors containing the CCL19 gene (Ad-CCL19) and combined them with PEG-PE [poly(ethylene glycol)-phosphatidylethanolamine]-modified cationic liposomes (Ad-CCL19/PEG-PE) for immunotherapy against murine fibrosarcoma. Although there were hardly any therapeutic differences between Ad-CCL19- and Ad-CCL19/PEG-PE-treated mice that were observed at the second administration, the final results demonstrated that Ad-CCL19/PEG-PE-treated mice survived much longer. The antitumour efficacy may be related to the high level of CCL19 after the final administration and lasting expression of IFN-gamma (interferon-gamma) and IL-12 (interleukin-12) in the Ad-CCL19/PEG-PE-treated group, which were measured by reverse-transcription PCR and ELISA. The results demonstrated that PEG-PE-cationic-liposome-conjugated adenovirus could prolong the expression of the therapeutic gene in vivo and may enhance the antitumour efficacy.

[Anti-tumor effects of recombinant adenovirus encoding survivin encapsulated in cationic liposome].

OBJECTIVE: To explore the anti-tumor effects and mechanisms of recombinant adenovirus encoding survivin encapsulated in cationic liposome. METHODS: CT26 tumor model was established in BALB/c mice. Fifty mice were randomly divided into five groups, including the group treated with recombinant adenovirus encoding survivin encapsulated in cationic liposome (Lip+ Ad-sur), the group of recombinant adenovirus encoding survivin (Ad-sur), the group of recombinant adenovirus encoding null encapsulated in cationic liposome (Lip+Ad-null), the group of liposome (Lip), and the group of PBS alone (PBS). Survival rate of mice, tumor volume, and side effects of treatments were observed. Lymphocytes were activated by adenovirus vaccine to kill tumor cells in vitro and in vivo. CTL assay and histological examination were carried out. RESULTS: Immunotherapy with recombinant adenovirus encoding survivin encapsulated in cationic liposome was effective for inducing protective and therapeutic anti-tumor immunity in CT26 tumor model. In the combination therapy group, the tumor growth was inhibited and the tumor volume was significantly smaller when compared with the controls. The survival rate of mice in the combination therapy group at 7 weeks after inoculation of tumor cells was significantly higher than that of the control group. Histologically, the tumor tissue was markedly necrotic and was infiltrated by lymphocytes. 51Cr assay in vitro indicated that the combination therapy group showed higher specific killing activity against CT26 tumor cells than did the control groups, and the T cells were independent of NK cells. CONCLUSION: Immunotherapy with recombinant adenovirus encoding survivin encapsulated in cationic liposome was noted to have a significant anti-tumor effect on CT26 tumor model.