Low-dose paclitaxel improves the therapeutic efficacy of recombinant adenovirus encoding CCL21 chemokine against murine cancer.

Secondary lymphoid tissue chemokine (SLC/CCL21), one of the CC chemokines, exerts potent antitumor immunity by co-localizing T cells and dendritic cells at the tumor site and is currently tested against human solid tumors. Here, we investigated whether the combination of recombinant adenovirus encoding murine CCL21 (Ad-mCCL21) with low-dose paclitaxel would improve therapeutic efficacy against murine cancer. Immunocompetent mice bearing B16-F10 melanoma or 4T1 breast carcinoma were treated with either Ad-mCCL21, paclitaxel, or both agents together. Our results showed that Ad-mCCL21 + low-dose paclitaxel more effectively reduced the growth of tumors as compared with either treatment alone and significantly prolonged survival time of the tumor-bearing animals. These antitumor effects of the combined therapy were linked to altered cytokine network at the tumor site, enhanced apoptosis of tumor cells, and decreased formation of new vessels in tumors. Importantly, the combined therapy elicited a strong therapeutic antitumor immunity, which could be partly abrogated by the depletion of CD4(+) or CD8(+) T lymphocytes. Collectively, these preclinical evaluations may provide a combined strategy for antitumor immunity and should be considered for testing in clinical trials.

Gene therapy using the human telomerase catalytic subunit gene promoter enables targeting of the therapeutic effects of vesicular stomatitis virus matrix protein against human lung adenocarcinoma.

The catalytic subunit of telomerase, human telomerase reverse transcriptase (hTERT), is highly active in immortalized cells and more than 90% of human cancer cells, but is quiescent in the majority of normal somatic cells. Thus, the hTERT promoter has been extensively used in targeted cancer gene therapy. Vesicular stomatitis virus (VSV) matrix protein (MP) induces the apoptosis of tumor cells in the absence of other viral components. In our previous studies, we successfully constructed the pVAX-M plasmid from the pVAX plasmid, which expressed wild-type VSV MP (VSV MP is under the control of the CMV promoter) and demonstrated that pVAX-M efficiently suppresses the growth of malignant tumors via the induction of apoptosis in vitro and in vivo. The present study was designed to construct the plasmid phTERTM (VSV MP is under the control of the hTERT promoter) and investigate whether it had a targeted antitumor effect in nude mice bearing human lung adenocarcinoma. In vitro, A549 human lung adenocarcinoma cells were treated with NS, Lip-null, etoposide, Lip-pVAX-M or Lip-phTERT-M, and examined for cell viability through MTT assays or for apoptosis by flow cytometry and TUNEL assays. In vivo, A549 human lung carcinoma models in nude mice were established. Mice were treated with 10 4-weekly intravenous administrations of NS, Lip-null, etoposide (2 mg/kg), Lip-pVAX-M or Lip-phTERT-M. Subsequently, Lip-phTERT-M was found to be the most efficient inhibitor of tumor growth and inducer of tumor cell apoptosis when compared with the other groups in vivo and in vitro (P<0.05). Notably, immunohistochemical staining showed that Lip-phTERT-M significantly limited the overexpression of VSV MP to the tumor tissues and reduced VSV MP expression in other organs in comparison with Lip-pVAX-M (P<0.05). Therefore, it can be concluded that phTERT-M demonstrates a targeted antitumor effect on A549 human lung adenocarcinoma cells. These observations suggest that phTERT-M gene therapy may be a novel and potent strategy for targeting human lung adenocarcinoma.

Diluted povidone-iodine inhibits tumor growth through apoptosis-induction and suppression of SOD activity.

Povidone-iodine (PVP-I) is widely used in clinical practice as an antiseptic and flushing agent after surgery to remove a tumor. Our present study was designed to determine whether diluted PVP-I is cytotoxic to colon cancer cells and ascetic tumor cells in vitro and to examine its antitumor effects in vivo. In vitro, CT26 and H22 cells treated with different concentrations of diluted PVP-I (0-1.56 µg/ml) were analyzed using the mononuclear cell direct cytotoxicity assay (MTT) and a flow cytometry assay. In vivo, Balb/c mice injected in the abdominal cavity with CT26 cells or H22 cells were treated intraperitoneally with different concentrations of PVP-I (0-312.5 µg/mouse), cisplatin (40 mg/kg) or 5'-FU (30 mg/kg) or left untreated. In vitro, the studies demonstrated the antiproliferative and significant apoptosis-inducing effects of PVP-I in a dose- and time-dependent manner. In vivo, PVP-I significantly repressed the growth of H22 and CT26 cells in Balb/c mice compared to controls. To explore the mechanism of the antitumor effect of PVP-I, the superoxide dismutase (SOD) activity of ascites extracted from a mouse model and the supernatant of CT26 cells was detected by an SOD kit. The activity of SOD was significantly inhibited in the experimental groups. Taken together, our data suggest that PVP-I exhibits a strong inhibitory effect on tumor growth in colon cancer (CT26) and hepatoma (H22) resulting from apoptosis, both in vitro and in vivo, suggesting a new potential therapeutic approach after tumor excision surgery to colon cancer and hepatoma.