A Whole-genome CRISPR Screen Identifies a Role of MSH2 in Cisplatin-mediated Cell Death in Muscle-invasive Bladder Cancer

Background

The response to first-line, platinum-based treatment of muscle-invasive bladder cancer has not improved in 3 decades.

铂类药物在头颈部鳞癌治疗中的选择与应用

以铂类药物为基础的化疗成为晚期头颈部鳞癌（head and neck squamous cell carcinoma，HNSCC）综合治疗中不可缺少的部分。化疗可与放疗同步用于局部晚期HNSCC的根治性治疗，或用于具有高危因素的HNSCC术后辅助治疗，也可用于诱导化疗（新辅助化疗）或者放疗后的辅助化疗。同期放化疗在局部晚期HNSCC的治疗中尤其重要。几种常用的铂类药物在HNSCC的治疗中各有优势。本文简述铂类药物的药理作用及机制，比较铂类药物在HNSCC的疗效与毒性，并分析不同给药方式（单药或多药联合，每周或每3周）与给药剂量所带来的疗效与毒性差异，希望能对医师合理使用铂类药物治疗HNSCC有所裨益。     

Mechanistic perspective of protective effects of nilotinib against cisplatin-induced testicular injury in rats: Role of JNK/caspase-3 signaling inhibition

Cisplatin is an effective anticancer used widely in treatment of solid and germ cell tumors, however, the immense toxicity on healthy tissues discourages cisplatin use in prolonged treatment protocols. Testicular toxicity is amongst its undesired adverse effects. Nilotinib is a second generation multityrosine kinase inhibitor which is used as an anticancer agent with anti-inflammatory and antioxidant activities. In the present study, a single dose of cisplatin (7 mg/kg, I.P) to rats induced a significant testicular injury. Daily administration of nilotinib (20 mg/kg, orally) 24 h post cisplatin injection for 10 days ameliorated testicular damage. Nilotinib significantly increased serum testosterone and sperm concentration outside frame of oligospermia with simultaneous full recovery of sperm viability. Nevertheless, biomarkers of apoptosis such as JNKs and Caspase -3, were significantly reduced. Moreover, improved antioxidant status of the testes was inferred by significant elevation of GSR, SOD and TAC alongside with reduction in lipid peroxidation biomarkers; MDA and 4-HNE. Flow Cytometry analysis of the cell cycle confirmed a significant increase in the percentage of testicular cells present in G2/M phase and a significant decrease in the percentage of apoptotic testicular cells after nilotinib administration. Histopathologically, nilotinib preserved testicular architecture showing significant numbers of sperm and spermatids within lumens of seminiferous tubule. Furthermore, nilotinib enhanced testicular expression of Ki67 significantly, providing evidence of testicular regeneration. In conclusion, nilotinib refinement of cisplatin induced testicular toxicity is attributed to enhancing antioxidant capabilities, decreasing apoptotic signals and restoring regenerative capacity of testes suggesting nilotinib to be used in conjunction with cisplatin in treatment protocols to avoid cisplatin induced long term testicular toxicity.     

The comparison of animal models for premature ovarian failure established by several different source of inducers

The objective of this study was to compare premature ovarian failure animal models established by several different source of inducers. Female ICR mice, KM mice, and SD rats were treated by cyclophosphamide at 120 mg/kg, busulfan at 12 mg/kg, cisplatin at 3 or 4 mg/kg, 4-vinylcyclohexene diepoxide at 160 mg/kg, 35% galactose food pellet, and tripterygium glycosides at 50 mg/kg, respectively. Parameters were analyzed by body weight, serum concentration level of related hormones, ovarian and uterine pathological examination. The results indicated the body weight of mice increased very slowly following single dose of cyclophosphamide (p < 0.05) with damaged ovary; repeated doses of cisplatin could induce body weight significantly decreased (p < 0.01) with a rising trend of serum LH concentration, declining tendency of serum E2 concentration and injured ovary and uterus; 4-vinylcyclohexene diepoxide also hindered the mice growing (p < 0.05) with damaged ovary and uterus; the body weight of mice feed by 35% galactose food pellet increased slowly (p < 0.05) with dramatically higher serum concentration level of galactose, albumin, and total protein (p < 0.001) and injured ovary. Busulfan and tripterygium glycosides did not present obvious evidences. In conclusion, the inducers presented their respective features in such animal models and should be appropriately applied in preventive methods.     

Feasibility and efficacy evaluation of metallic biliary stents eluting gemcitabine and cisplatin for extrahepatic cholangiocarcinoma

BACKGROUND Effective endoscopic management is fundamental for the treatment of extrahepatic cholangiocarcinoma(ECC). However, current biliary stents that are widely used in clinical practice showed no antitumor effect. Drug-eluting stents(DESs) may achieve a combination of local chemotherapy and biliary drainage to prolong stent patency and improve prognosis.AIM To develop novel DESs coated with gemcitabine(GEM) and cisplatin(CIS)-coloaded nanofilms that can maintain the continuous and long-term release of antitumor agents in the bile duct to inhibit tumor growth and reduce systemic toxicity.METHODS Stents coated with different drug-eluting components were prepared by the mixed electrospinning method, with poly-L-lactide-caprolactone(PLCL) as the drug-loaded nanofiber membrane and GEM and/or CIS as the antitumor agents. Four different DESs were manufactured with four drug-loading ratios(5%, 10%, 15%, and 20%), including bare-loaded(PLCL-0), single-drug-loaded(PLCL-GEM and PLCL-CIS), and dual-drug-loaded(PLCL-GC) stents. The drug release property, antitumor activity, and biocompatibility were evaluated in vitro and in vivo to confirm the feasibility and efficacy of this novel DES for ECC.RESULTS The in vitro drug release study showed the stable, continuous release of both GEM and CIS, which was sustained for over 30 d without an obvious initial burst, and a higher drug-loaded content induced a lower release rate. The drug-loading ratio of 10% was used for further experiments due to its ideal inhibitory efficiency and relatively low toxicity. All drug-loaded nanofilms effectively inhibited the growth of EGI-1 cells in vitro and the tumor xenografts of nude mice in vivo; in addition, the dual-loaded nanofilm(PLCL-GC) had a significantly better effect than the single-drug-loaded nanofilms(P 0.05). No significant differences in the serological analysis(P 0.05) or histopathological changes were observed between the single-loaded and drug-loaded nanofilms after stent placement in the normal porcine biliary tract.CONCLUSION This novel PLCL-GEM and CIS-eluting stent maintains continuous, stable drug release locally and inhibits tumor growth effectively in vitro and in vivo. It can also be used safely in normal porcine bile ducts. We anticipate that it might be considered an alternative strategy for the palliative therapy of ECC patients.     

Traitement systémique des métastases cérébrales de cancer bronchique

Systemic treatment of lung cancer patients with brain metastases is based on clinical (presence of symptomatic intracranial lesions), pathological and molecular characteristics of the disease. The efficacy of standard platinum-based chemotherapy is comparable inside and outside the brain, justifying its use as front-line therapy. The intracranial efficacy of targeted therapies (EGFR tyrosine kinase inhibitors, ALK inhibitors) is demonstrated, and is globally superior to the efficacy of standard chemotherapy, justifying their use as front-line therapy in case of EGFR activating mutation or ALK rearrangement (providing the change in the crizotinib label in France). The concomitant use of whole brain radiotherapy and a systemic treatment (chemotherapy or targeted therapy) is not recommended in the absence of a demonstrated better efficacy and/or acceptable safety profile. Several trials are ongoing to assess new whole brain radiotherapy modalities, new targeted therapies alone or in combination, especially exploring immunotherapy.     

Low-dose all-trans retinoic acid enhances cytotoxicity of cisplatin and 5-fluorouracil on CD44+ cancer stem cells

Cis-diamminedichloridoplatinum(II)(CDDP)-based combination chemotherapy is frequently used in gastrointestinal cancer. The synergistic mechanism of all-trans retinoic acid (ATRA), cisplatin (CDDP) and 5-fluorouracil (5-FU) in combination remains unclear. Despite their potent antitumor properties, resistance to CDDP and 5-FU develops frequently in tumors. To clarify this mechanism, we determined the sensitivity to each drug and their combination in two gastrointestinal cancer stem cells (CSCs) subpopulation.Here, we report the identification and separation of CD44⁺ cells from human gastric carcinoma (AGS) and human esophageal squamous cell carcinoma (KYSE-30) cancer cell lines by magnetic activated cell sorting (MACS). We allowed the CD44^± cells to grow 6 days at a subtoxic concentration of ATRA and then treated with different concentration of CDDP and 5-FU for 24 h. The cytotoxicity was examined by cell proliferation MTT assay. Additionally, AO/EB staining was used for detection of apoptotic cells. In order to determine whether the growth inhibition was also associated with changes in cell cycle distribution, cell cycle analysis was performed using flow cytometry.Low concentration of ATRA (1 μM, 6days) followed by 5-FU and CDDP was found to be more effective than either drugs alone, thus resulting in synergistic cytotoxicity in Kyse-30 and AGSCD44^± cells. Furthermore, there was an indication that the combination of ATRA with 5FU and CDDP caused an increase in cell cycle arrest in G2/M and G0/G1.We conclude that low concentration of ATRA enhances the cytotoxicity of CDDP and 5FU by facilitating apoptosis and cell cycle arrest in gastrointestinal CSCs and provide a rational basis for the design of novel, well-tolerated CDDP- and 5FU-based chemotherapy in human gastrointestinal carcinoma.