Yan-Qun Liu

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.

Combining conditionally replicating adenovirus-mediated gene therapy with chemotherapy: a novel antitumor approach

Despite significant improvements in diagnosis and innovations in the therapy of specific cancers, effective treatment of neoplastic diseases still presents major challenges. Recent studies have shown that 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. Several studies in animal models have demonstrated that the combination of CRAds‐mediated gene therapy and chemotherapy has greater therapeutic benefit than either treatment modality alone. In this review, an overview of specifications for a novel antitumor approach combining CRAd‐gene therapy and chemotherapy is provided and recent progress in this field is discussed.

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.

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.

Advances on chimeric antigen receptor-modified T-cell therapy for oncotherapy

Tumor treatment is still complicated in the field of medicine. Tumor immunotherapy has been the most interesting research field in cancer therapy. Application of chimeric antigen receptor T (CAR-T) cell therapy has recently achieved excellent clinical outcome in patients, especially those with CD19-positive hematologic malignancies. This phenomenon has induced intense interest to develop CAR-T cell therapy for cancer, especially for solid tumors. However, the performance of CAR-T cell treatment in solid tumor is not as satisfactory as that in hematologic disease. Clinical studies on some neoplasms, such as glioblastoma, ovarian cancer, and cholangiocarcinoma, have achieved desirable outcome. This review describes the history and evolution of CAR-T, generalizes the structure and preparation of CAR-T, and summarizes the latest advances on CAR-T cell therapy in different tumor types. The last section presents the current challenges and prospects of CAR-T application to provide guidance for subsequent research.

Dacarbazine Combined Targeted Therapy versus Dacarbazine Alone in Patients with Malignant Melanoma: A Meta-Analysis

Background Malignant melanoma is the most aggressive and deadly form of skin cancer. Dacarbazine (DTIC) has been the approved first-line treatment for metastatic melanoma in routine clinical practice. However, response rates with single-agent DTIC are low. The objective of this study was to compare the efficacy and safety of DTIC with or without placebo and DTIC-based combination therapies in patients with advanced metastatic melanoma. Methods We searched from electronic databases such as The Cochrane Library, MEDLINE, EBSCO, EMBASE, Ovid, CNKI, and CBMDisc from 2003 to 2013. The primary outcome measures were overall response and 1-year survival, and the secondary outcome measurements were adverse events. Results Nine randomized controlled trials (RCTs) involving 2,481 patients were included in the meta-analysis. DTIC-based combination therapies was superior to DTIC alone in overall response (combined risk ratio [RR]  = 1.60, 95% confidence interval [CI]: 1.27–2.01) and 1-year survival (combined RR = 1.26, 95% CI: 1.14–1.39). Patients with DTIC-based combination therapies had higher incidence of adverse events including nausea (combined RR = 1.23, 95% CI: 1.10–1.36), vomiting (combined RR = 1.73, 95% CI: 1.41–2.12) and neutropenia (combined RR = 1.75, 95% CI: 1.42–2.16) compared to the group for DTIC alone. Conclusion These data suggested that DTIC-based combination therapies could moderately improve the overall response and the 1-year survival but increased the incidence of adverse events. Further large-scale, high-quality, placebo-controlled, double-blind trials are needed to confirm this conclusion.

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

Abstract 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.

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.

Down-regulation of O6-methylguanine-DNA methyl transferase enhances the effect of temozolomide in melanoma cells.

reduced AVP secretion. In conclusion, because decrease of vasopressin occurs during a spontaneous episode of MoA, it might therefore be considered as one of the causes of PNE in MoA which is described as multifactorial influences. However, further studies are necessary to elucidate which migraine would be responsible for PNE and what molecular mechanisms are involved in altered hypothalamic activity resulting in reduced vasopressin secretion in children with MoA. The concentration-dependent effect, the precise role of vasopressin in aberrations of regional cerebral blood flow in migraine [5] and biphasic secretion of vasopressin during an attack of migraine should also be further evaluated in the future.