Recent developments in nanomedicine for melanoma treatment.

Melanoma is a most aggressive skin cancer with limited therapeutic options and its incidence is increasing rapidly in recent years. The discovery and application of new targeted therapy agents have shown significant benefits. However, adverse side-effects and resistance to chemotherapy remain formidable challenges in the clinical treatment of malignant melanoma. Nanotherapeutics offers an important prospect of overcoming these drawbacks. The anti-tumoral applications of nanomedicine are varied, including those in chemotherapy, RNA interference, photothermal therapy, and photodynamic therapy. Furthermore, nanomedicine allows delivery of the effector structures into the tumor site via passive or active targeting, thereby allowing increased therapeutic specificity and reduced side effects. In this review, we summarize the latest developments in the application of nanocarrier-mediated targeted drug delivery to melanoma and nanomedicine-related clinical trials in melanoma treatment. We also discuss existing problems and opportunities for future developments, providing direction and new thoughts for further studies.

Insecticidal Constituents from Buddlej aalbiflora Hemsl.

Eleven known compounds, deoxymikanolide (1), 1,3-dihydroxyxanthone (2), kumatakenin (3), apigenin (4), chrysin (5), kaempferol (6), Iso-kaempferol (7), luteolin (8), luteolin-3',4'-dimethylether-7-O-ß-glucoside (9), luteolin-7-O-ß-glucoside (10) and quercetin (11) were identified in MeOH extract of Buddleja albiflora Hemsl (Oleaceae). These compounds (each, 1, 0.5 and 0.25 mg mL-1) were tested for insecticidal activity against 3rd and 4th-instar larvae of Plutella xylostella, 3rd-instar larvae of Mythimna separata and 3rd-instar larvae of Macrosiphoniella sanborni. The lowest 50% anti-feedant concentration (AFC50) against P. xylostella and 50% lethal concentration (LC50) against P. xylostella and M. sanborni were observed as 0.0058, 0.0046 and 3.4048 mg L-1, respectively.

Application of Nanotechnology in the Diagnosis and Therapy of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. However, the inherent limitations of traditional surgery and insensitivity to radiation and chemotherapy result in failing treatment and poor prognosis. In recent years, the development and advances of nanotechnology has brought new hope for the diagnosis and treatment of HCC. This article reviews the development of nanoparticles used for cancer detection, diagnosis and treatment due to their large specific surface area and unique optical, electronic and magnetic properties. Moreover, studies have shown that after intended surface modification, nano-carriers can achieve active targeting effect, which improves the efficiency of chemotherapeutic drugs and decreases their side effects. In this review, we provide an overview of these studies results, patents about novel nanomaterials and conclude with a discussion about future development.

Enhanced antitumor efficacy of a novel oncolytic adenovirus combined with temozolomide in the treatment of melanoma in vivo.

PURPOSE: The aim of this study was to investigate the effect of Ki67-ZD55-IL-24 with temozolomide (TMZ) against melanoma in mice. METHODS: Seventy-eight mice with subcutaneous injection of A375 cells (2 × 10(6)) into the right flank were randomized to receive phosphate buffered saline (PBS), Ki67-ZD55, Ki67-ZD55-IL-24, TMZ, TMZ + Ki67-ZD55, and TMZ + Ki67-ZD55-IL-24. Six mice were killed in each group 10 days after intervention for detecting IL-24 mRNA and protein expression. The remaining mice were monitored to draw the body weight change curve and tumor growth curve, and killed 30 days after intervention. Tumors were excised and weighted. The morphology of tumor tissues was determined by hematoxylin and eosin (HE) staining, and the apoptosis index and rate of apoptotic cells were determined by TUNEL assay and AnnexinV-FITC/PI double staining, respectively. RESULTS: The Ki67-ZD55-IL-24-treated group generated much more reactive oxygen species than the untreated group. There was no significant difference in IL-24 expression between Ki67-ZD55-IL-24 and TMZ + Ki67-ZD55-IL-24 groups. Immunohistochemical analysis and Western blot revealed that both the Ki67-ZD55 and Ki67-ZD55-IL-24 could significantly reduce the expression of MGMT. Toxicity assessments demonstrated that mice in the three groups that received TMZ exhibited significant body weight loss following treatment. HE staining showed that TMZ + Ki67-ZD55-IL-24 group had much fewer karyokinesis in the tumors, compared with other groups. The apoptosis index of tumor tissues and the rate of apoptotic cells were significantly higher in TMZ + Ki67-ZD55-IL-24 group than in other groups (all P < 0.05). CONCLUSIONS: These findings indicate this novel strategy holds promising potentials for treatment of malignant melanoma.

A conditionally replicating adenovirus carrying interleukin-24 sensitizes melanoma cells to radiotherapy via apoptosis.

Combinatorial therapy is the current trend of the development of novel cancer treatments due to the high heterogenous nature of solid tumors. In this study, we investigated the effects of the combined use of a conditionally replicating adenovirus carrying IL-24 (ZD55-IL-24) and radiotherapy on the proliferation and apoptosis of melanoma A375 cells in vitro and in vivo. Compared with either agent used alone, ZD55-IL-24 combined with radiotherapy significantly inhibited cell proliferation, accompanied with increased apoptosis. Radiotherapy did not affect the expression of IL-24 and E1A of ZD55-IL-24-treated cells, but increased the expression of Bax, promoted the activation of caspase-3, while decreasing Bcl-2 levels. Thus, this synergistic effect of ZD55-IL-24 in combination with radiotherapy provides a novel strategy for the development of melanoma therapies, and is a promising approach for further clinical development.

Conditionally replicating adenoviruses carrying mda-7/IL-24 for cancer therapy.

BACKGROUND: Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) suppresses growth and induces apoptosis in a broad range of human cancers without significant cytotoxicity to normal cells. Conditionally replicating adenoviruses (CRAds) not only have the ability to destroy cancer cells but may also be potential vectors for the expression of therapeutic genes. METHODS: This review provides an overview of specifications for a novel anti-tumor approach CRAds carrying IL-24, and discusses recent progress in this field. RESULTS: Studies in multiple laboratories report that CRAds carrying IL-24 selectively induced apoptosis in some cancer cells, and enhanced selective toxicity to cancer cells when combined with chemotherapeutic agents. CONCLUSION: CRAds carrying IL-24 may prove a novel and effective approach for the treatment of cancers.

A novel approach to overcome temozolomide resistance in glioma and melanoma: Inactivation of MGMT by gene therapy.

Malignant glioma is the most common primary brain tumor. Malignant melanoma is the most malignant of skin tumor. The two malignancies are poorly responsive to conventional treatment regimens such as chemotherapy. Temozolomide (TMZ) is a DNA-alkylating agent used for the treatment of glioma, astrocytoma, and melanoma. Resistance to alkylating agents such as TMZ correlates with increased expression of DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Several studies in animal models have demonstrated that decreasing MGMT level with gene therapy could overcome TMZ resistance and enhance tumor cell death. In the present review, we provide an overview of recent advances in this field.

Enhanced anti-tumor activity by the combination of a conditionally replicating adenovirus mediated interleukin-24 and dacarbazine against melanoma cells via induction of apoptosis.

Malignant melanoma is one of the most lethal and aggressive human malignancies. It is notoriously resistant to all of the current therapeutic modalities, including chemotherapy. Suppressed apoptosis and extraordinary invasiveness are the distinctive features that contribute to the malignancy of melanoma. Dacarbazine (DTIC) has been considered as the gold standard for melanoma treatment with a response rate of 15-20%. Unfortunately, the resistance to this chemotherapeutic agent occurs frequently. ZD55-IL-24 is a selective conditionally replicating adenovirus that can mediate the expression of interleukin-24 (IL-24) gene, which has a strong anti-tumor effect. In this study, we hypothesized that a combination of ZD55-IL-24-mediated gene virotherapy and chemotherapy using DTIC would produce an increased cytotoxicity against human melanoma cells in comparison with these agents alone. Our results showed that the combination of ZD55-IL-24 and DTIC significantly enhanced the anti-tumor activity by more effectively inducing apoptosis in melanoma cells than either agent used alone without any overlapping toxicity against normal cells. This additive or synergistic effect of ZD55-IL-24 in combination with DTIC in killing human malignant melanoma cells implies a promising novel approach for melanoma therapy.

[Urticaria in relation to mite sensitivity and immunotherapy with Injection dermatophagoidei farinae].

OBJECTIVE: To investigate the prevalence of mite sensitivity in patients with urticaria or other skin rashes, and to observe the clinical efficacy of a specific immunotherapy (SIT) by the Injection dermatophagoides farinae for the patients. METHODS: In 7-year period (1998-2005), skin prick test (SPT) with a dust mite (Df) allergen was carried out to detect the prevalence of mite sensitivity in OPD patients suffering from skin rashes. Among the patients sensitive to mite with SPT > or =++ response, 3 groups were established. In group A, routine SIT with Injection dermatophagoides farinae was conducted. In 9-week increasing dose phase, three stepwise increasing volumes (0.3 ml, 0.6 ml and 1.0 ml) each case was injected subcutaneously with mite concentration of 1:100000 (w/v), 1:10000 (w/v) or 1:5000 (w/v) respectively once a week, followed by a maintenance dose phase for an injection with 1:5000 (w/v) 1.0 ml/wk for 6 weeks. Group B received rush SIT with mite injections. A total of 15 injections in a course of therapy with same concentration and volume was given as those for the routine ones except shortened intervals, namely, 9 initial injections completed in 3 days by three injections of each concentration per day with two 30 min intervals, maintenance doses were then provided in 6 days with 1:5000 (w/v) 1.0 ml/d. Thereafter, both groups A and B were maintained for one year with a dose of 1:5000 (w/v) 1.0 ml every 2 wk. Group C received antihistamine treatment as control, the patients received daily oral Ebastine 10 mg in the morning and Cetirizine dihydrochloride 10 mg in the evening for one week course and pro re nata later. Levels of serum tIgE and serum mite sIgE were detected by ELISA in 20 urticaria cases before and after one year mite SIT. RESULTS: Altogether, 2685 cases with skin rashes were detected by Df allergen SPT. The prevalence of urticaria cases sensitive to mite was 70.3% (1754/2496), which was higher than that of eczema 63.5% (54/85) and anaphylactoid purpura 60.6% (63/104) (P < 0.05) . 248 cases of urticaria sensitive to mite with SPT > or = ++ response received SIT with Injection dermatophagoides farinae for one year, clinical evaluation revealed an overall efficacy of 91.1% (226/248) with 66.1% (164/248) of excellent or good results, significantly higher than that of antihistamine treatment [12.7% (20/158)] (P < 0.01). Faster improvement of clinical symptoms was shown in rush SIT (group B) than that of routine one (group A), with higher efficacy in group B than group A (excellent and good results being 76.7% and 55.0% respectively) (P < 0.05). Serum tIgE and mite sIgE in 20 urticaria cases were detected before and after one year mite SIT, showing that tIgE decreased by half in 40% (8) of the patients, while serum mite sIgE level increased significantly (P < 0.01) one year later. CONCLUSION: Mite allergen SPT is an etiological diagnostic technique for urticaria patients sensitive to mite. Clinical efficacy of mite allergen SIT has been proved to be good for the patients, and the rush SIT shows quicker effect of relieving symptoms and better efficacy than that of the routine immunotherapy.