Molecular landscape and subtype-specific therapeutic response of nasopharyngeal carcinoma revealed by integrative pharmacogenomics.

Nasopharyngeal carcinoma (NPC) is a malignant head and neck cancer type with high morbidity in Southeast Asia, however the pathogenic mechanism of this disease is poorly understood. Using integrative pharmacogenomics, we find that NPC subtypes maintain distinct molecular features, drug responsiveness, and graded radiation sensitivity. The epithelial carcinoma (EC) subtype is characterized by activations of microtubule polymerization and defective mitotic spindle checkpoint related genes, whereas sarcomatoid carcinoma (SC) and mixed sarcomatoid-epithelial carcinoma (MSEC) subtypes exhibit enriched epithelial-mesenchymal transition (EMT) and invasion promoting genes, which are well correlated with their morphological features. Furthermore, patient-derived organoid (PDO)-based drug test identifies potential subtype-specific treatment regimens, in that SC and MSEC subtypes are sensitive to microtubule inhibitors, whereas EC subtype is more responsive to EGFR inhibitors, which is synergistically enhanced by combining with radiotherapy. Through combinational chemoradiotherapy (CRT) screening, effective CRT regimens are also suggested for patients showing less sensitivity to radiation. Altogether, our study provides an example of applying integrative pharmacogenomics to establish a personalized precision oncology for NPC subtype-guided therapies.

Danshensu, a major water-soluble component of Salvia miltiorrhiza, enhances the radioresponse for Lewis Lung Carcinoma xenografts in mice.

The molecule 3-(3,4-dihydroxyphenyl)-2-hydroxypropanoic acid (danshensu), a herbal preparation used in traditional Chinese medicine, has been found to possess potential antitumor and anti-angiogenesis effects. The aim of the present study was to investigate the efficacy of the combination of radiation therapy (RT) with danshensu in the treatment of Lewis lung carcinoma (LLC) xenografts, whilst exploring and evaluating the mechanism involved. In total, 8-week old female C57BL/6J mice were randomly assigned into 3 groups to receive: RT, RT + cisplatin and RT + danshensu, respectively, when LLC reached 100-150 mm3. Each group was divided into 7 subgroups according to the different irradiation doses that were administered. Tumor growth curves were created and the sensitization enhancement ratios of the drugs were calculated. The experiment was then repeated, and the 4 groups of tumor-bearing mice were treated with natural saline, danshensu, RT + danshensu and RT, respectively. The mice were sacrificed on day 7, and tumor tissue and blood were collected to determine microvessel density, the expression of proangiogenic factors, and the levels of blood thromboxane B2 and 6-keto-prostaglandin-F1α. Tumor hypoxia was also detected using in vivo fluorescence imaging. With respect to LLC xenografts, treatment with danshensu + RT significantly enhanced the effects of tumor growth inhibition (P<0.05). Furthermore, tumor vasculature was remodeled and microcirculation was improved, which significantly reduced tumor hypoxia (P<0.05). The present study demonstrated that danshensu significantly enhanced the radioresponse of LLC xenografts in mice. The mechanism involved may be associated with the alleviation of tumor cell hypoxia following treatment with danshensu + RT, caused by the improvement of tumor microcirculation and the remodeling of tumor vasculature.

Preparation of endostatin-loaded chitosan nanoparticles and evaluation of the antitumor effect of such nanoparticles on the Lewis lung cancer model.

The purpose of this study was to prepare ES-loaded chitosan nanoparticles (ES-NPs) and evaluate the antitumor effect of these particles on the Lewis lung cancer model. ES-NPs were prepared by a simple ionic cross-linking method. The characterization of the ES-NPs, including size distribution, zeta potential, loading efficiency and encapsulation efficiency (EE), was performed. An in vitro release test was also used to determine the release behavior of the ES-NPs. Cell viability and cell migration were assayed to detect the in vitro antiangiogenic effect of ES-NPs. In order to clarify the antitumor effect of ES-NPs in vivo, the Lewis lung cancer model was used. ES-NPs were successfully synthesized and shown to have a suitable size distribution and high EE. The nanoparticles were spherical and homogeneous in shape and exhibited an ideal releasing profile in vitro. Moreover, ES-NPs significantly inhibited the proliferation and migration of human umbilical vascular endothelial cells (HUVECs). The in vivo antiangiogenic activity was evaluated by ELISA and immunohistochemistry analyses, which revealed that ES-NPs had a stronger antiangiogenic effect for reinforced anticancer activity. Indeed, even the treatment cycle in which ES-NPs were injected every seven days, showed stronger antitumor effect than the free ES injected for 14 consecutive days. Our study confirmed that the CS nanoparticle is a feasible carrier for endostatin to be used in the treatment of lung cancer.

Effect of Kangfuxin Solution on Chemo/Radiotherapy-Induced Mucositis in Nasopharyngeal Carcinoma Patients: A Multicenter, Prospective Randomized Phase III Clinical Study.

Objective. To evaluate the efficacy and safety of Kangfuxin Solution, a pure Chinese herbal medicine, on mucositis induced by chemoradiotherapy in nasopharyngeal carcinoma patients. Methods. A randomized, parallel-group, multicenter clinical study was performed. A total of 240 patients were randomized to receive either Kangfuxin Solution (test group) or compound borax gargle (control group) during chemoradiotherapy. Oral mucositis, upper gastrointestinal mucositis, and oral pain were evaluated by Common Terminology Criteria for Adverse Events (CTCAE) v3.0 and the Verbal Rating Scale (VRS). Results. Of 240 patients enrolled, 215 were eligible for efficacy analysis. Compared with the control group, the incidence and severity of oral mucositis in the test group were significantly reduced (P = 0.01). The time to different grade of oral mucositis occurrence (grade 1, 2, or 3) was longer in test group (P < 0.01), and the accumulated radiation dose was also higher in test group comparing to the control group (P < 0.05). The test group showed lower incidence of oral pain and gastrointestinal mucositis than the control group (P < 0.01). No significant adverse events were observed. Conclusion. Kangfuxin Solution demonstrated its superiority to compound borax gargle on mucositis induced by chemoradiotherapy. Its safety is acceptable for clinical application.

Functional Chitosan Nanoparticles in Cancer Treatment.

With exponential growth in nanotechnology and material chemistry, the application of a variety of nanomaterials in biomedical field has attracted increasing interest, especially in cancer diagnosis and treatment. Nanoparticles have greatly revolutionized the therapy pattern of cancer owing to their specific targeting ability, prolonged circulation time, enhanced therapeutic efficacy, and decreased systemic side effects. Chitosan, a modified natural polysaccharide with excellent biocompatibility, has been intensively studied for use as carriers to deliver various drugs and genes in cancer treatment. This review provides an insight into the advances in chitosan-based nanoparticles with a focus on its therapeutic potential in cancer treatment.

Comparing radiotherapy with or without intracavitary hyperthermia in the treatment of primary nasopharyngeal carcinoma: a retrospective analysis.

AIMS AND BACKGROUND: A retrospective study was performed to evaluate the contribution of intracavitary hyperthermia in patients with nasopharyngeal carcinoma who received radiation therapy. METHODS AND STUDY DESIGN: Patients with nasopharyngeal carcinoma were treated with radiotherapy alone or with radiotherapy plus hyperthermia of the primary tumor. All patients were treated in a uniform fashion by definitive-intent radiotherapy in both groups. In the radiotherapy plus hyperthermia group, patients were treated with microwave heating hyperthermia delivered twice a week in combination with radiation. RESULTS: Between November 1992 to September 1994, 225 patients were recruited, with 98 patients matched to the criteria of either treatment group (49 in the radiotherapy and 49 in the radiotherapy plus hyperthermia group). Ninety-eight patients were included in the treatment response and 87 patients in the survival analysis according to the intent-to-treat principle (11 patients were lost to follow-up). Overall survival did not show a significant difference between the two groups (81 vs 86 months of median survival time, respectively, P = 0.068). However, there were significant differences not only in progression-free survival (median months, 60 vs 100, respectively, P = 0.036), but also in local progression-free survival (median months, 54 vs 111, respectively, P = 0.029) between the radiotherapy and radiotherapy plus hyperthermia groups. No statistical difference was noted in the cumulative incidence of grade 3 adverse events or late radiation morbidity during follow-up between the two study groups. CONCLUSIONS: The retrospective study showed that hyperthermia combined with radiation therapy can improve progression-free survival and local progression-free survival, although no increase in overall survival was observed. Thus, the inclusion of hyperthermia in the treatment of nasopharyngeal carcinoma using radiation offers no survival benefit but may help to improve the current standard of care consisting of radiation and chemotherapy.

Synergistic effect of combination topotecan and chronomodulated radiation therapy on xenografted human nasopharyngeal carcinoma.

PURPOSE: To investigate the in vivo chronomodulated radiosensitizing effect of topotecan (TPT) on human nasopharyngeal carcinoma (NPC) and its possible mechanisms. METHODS AND MATERIALS: Xenografted BALB/c (nu/nu) NPC mice were synchronized with an alternation of 12 hours of light from 0 to 12 hours after light onset (HALO) and 12 hours of darkness to establish a unified biological rhythm. Chronomodulated radiosensitization of TPT was investigated by analysis of tumor regrowth delay (TGD), pimonidazole hydrochloride, histone H2AX phosphorylation, (γ-H2AX) topoisomerase I (Top I), cell cycle, and apoptosis after treatment with (1) TPT (10 mg/kg) alone; (2) radiation therapy alone (RT); and (3) TPT+RT at 3, 9, 15, and 21 HALO. The tumor-loaded mice without any treatment were used as controls. RESULTS: The TPT+RT combination was more effective than TPT or RT as single agents. The TPT+RT combination at 15 HALO was best (TGD = 58.0 ± 3.6 days), and TPT+RT at 3 HALO was worst (TGD = 35.0 ± 1.5 days) among the 4 TPT+RT groups (P<.05). Immunohistochemistry analysis revealed a significantly increased histone H2AX phosphorylation expression and decreased pimonidazole hydrochloride expression in the TPT+RT group at the same time point. The results suggested that the level of tumor hypoxia and DNA damage varied in a time-dependent manner. The expression of Top I in the TPT+RT group was also significantly different from the control tumors at 15 HALO (P<.05). Cell apoptosis index was increased and the proportion of cells in S phase was decreased (P<.05) with the highest value in 15 HALO and the lowest in 3 HALO. CONCLUSIONS: This study suggested that TPT combined with chronoradiotherapy could enhance the radiosensitivity of xenografted NPC. The TPT+RT group at 15 HALO had the best therapeutic effect. The chronomodulated radiosensitization mechanisms of TPT might be related to circadian rhythm of tumor hypoxia, cell cycle redistribution, DNA damage, and expression of Top I.

In vitro mineralization of hydroxyapatite on electrospun poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) fibrous scaffolds for tissue engineering application.

In this study, a fibrous scaffold was prepared by electrospinning triblock PCL-PEG-PCL (PCEC) copolymer. Afterwards, in vitro biomimetic mineralization was carried out through incubation of the PCEC fibrous mats in a simulated body fluid (SBF) for different time. The apatite-deposited PCEC composite scaffolds were characterized by using Fourier-transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), scanning electron microscope (SEM) observation and weighing. Due to the importance of biocompatibility, rat ROS 17/2.8 osteoblasts were cultured on mineralized PCEC scaffolds, and the cell proliferation was investigated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assays. The obtained results confirmed that the deposited apatite had the chemical composition and crystalline phase similar to those of hydroxyapatite (HA). After 21 days incubation, the mass increase of PCEC scaffold reached up to 22%. Moreover, in vitro cell culture also confirmed that osteoblasts could attach on the mineralized composite scaffolds, and the HA-deposited PCEC mats had less cytotoxicity. So, the mineralized PCEC composite scaffolds had a great potential for tissue engineering application.

[Progress in research on constituents and pharmacological activities of sarcotestas of Ginkgo biloba].

The latest progress in research on constituents and pharmacological activities of sarcotestas of Ginkgo biloba has been studied. The main constituents in sarcotestas of G. biloba include flavones, ginkgolides, alkylphenols, polysaccharides and amino acids, etc. They show the following activities, such as bacteriostatic, bactericidal and pesticidal activities, antitumor and mutagenic, carcinogenic effects, antianaphylaxis and allergenic activity, effects on immunologic function, scavenging free radical, antisenile action, etc. The problems at present and the reseach direction for the future on sarcotestas of G. biloba have been put forward.