| BackgroundCervical cancer(CC)and Endometrial cancer(EC)are the most common gynaecological cancers in the world.with the development of the modem medicine,the traditional therapy of EC:surgery,radiotherapy and chemotherapy,have made great progress.however,all the therapies cannot solve the problem of recurrence and metastasis,and result in low response rates and survival benefit for patients with high-graded,metastatic or recurrent CC and EC.there is a pressing need for innovative therapies against CC and EC.Oncolytic viruses are wild or engineered viruses which initiate a multi-faceted cancer attack:they mediate immediate cancer cell lysis and subsequently release the tumor associated antigens which induce the immune clearance against the tumor.To date,oncolytic virotherapy is gaining growing interests as a novel therapeutic approach to treat cancers becauseof the high sensitivity and specificity,low toxicity.Coxsackievirus B3(CVB3)is a small,nonenveloped,positive-strand RNA enterovirus and has previously been demonstrated to possess potent oncolytic activity against various human cancer.Concerning CC and EC,however,the reports on CVB3 application are sparse so far.The aim of this study is to evaluate the oncolytic efficacy of CVB3 in both CC and EC,and to investigate its potential application as a novel biotherapeutic agent against CC and EC.Methods:1.The expressions of CVB3 receptors in human CC and EC cell lines were measured in vitro to estimate the susceptibilities of the two cancers to CVB3 infection.2.The oncolytic ability of CVB3 in vitro in human CC and EC cell lines were assessed with microscopes,cck8 and Crystal Violet staining.3.The oncolytic ability of CVB3 in vivo in nude mice bearing unilateral CC and EC xenografts was assessed,which were treated with either single dose or five consecutive doses of intratumoral CVB3.We also evaluatedThe systemic oncolytic effect of CVB3 against CC and EC was also assessed in a nude mouse model with bilateral xenografts which were treated through either one side intratumoral injection or tail vein injection4.The relationship of the oncolytic ability of CVB3 with cell apoptosis was investigated using Annexin V-PI staining.5.CVB3-induced oncolysis in fresh patient-derived CC and EC samples ex vivo was also evaluated.Results:1.All human CC cell lines:HeLa、Siha、Caski、C-33A and EC cell lines:HEC-1-A、HEC-1-B、Ishikawa,used in the study,expressed CVB3 receptors and were susceptible to lytic infection by CVB3 in vitro.2.The results of the oncolytic abilities of CVB3 detected with microscopes,cck8 and Crystal Violet staining in vitro were consistent,which showed that CVB3 demonstrated potential oncolytic activity in all CC and EC cell lines and the the oncolytic effect of CVB3 was proportional to MOI,but better in Hela、Caski、C-33A and HEC-1-B,Ishikawa cell lines.3.In the human unilateral CC xenograft/nude mouse model,a single dose of intratumoral CVB3 resulted in marked growth inhibition in HeLa and C-33A tumors but failed to control in Siha tumors,That was identical with what the five consecutive doses did.In the human unilateral EC xenograft/nude mouse model,five consecutive doses of intratumoral CVB3 resulted in marked growth inhibition in HEC-1-B and Ishikawa tumors but failed to control HEC-1-A tumors,Which was better than a single dose and consistent with the result in vitro.Additionally,CVB3 treatments suppressed not only the injected leisions but also the distant untreated ones.4.Apotosis happened in both CC and EC cell Lines infected with CVB3.5.Furthermore,CVB3 treatment resulted in decreased viability in ex vivo cultured patientderived CC and EC samples which was illuminated with Histoculture Drug Respones Assay.Conclusion:CVB3 showed potential oncolytic activity in human CC and EC cell lines both in vitro and in vivo,and samely confirmed in fresh patient-derived CC and EC samples.CVB3 virotherapy,with further improvements,holds the promise to serve as a new approach for the treatments of CC and EC. |
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