The Anti-tumor Effectiveness Of Vesicular Stomatitis Virus Matrix Protein Gene Combined With Hyperthermia In Mice

Objective: Vesicular Stomatitis Virus (VSV) has potential for inducing apoptosis in host cells. Previous studies showed that one VSV product, the matrix (M) protein, can directly induce apoptosis by inhibiting host gene expression when expressed in the absence of other viral components. Our lab first confirmed the M protein gene ofVSV complexed to DOTAP- cholesterol liposome(Lip-MP) suppress malignant tumor growth in vitro and in vivo. Hyperthermia (HT) is classically viewed as a form of adjuvant therapy forcancer in the clinic. In vitro and in vivo investigation showed that hyperthermia directly kills malignant cell by changing tumor microcirculation to induce necrosis and apoptosis. Additionally, hyperthermia has been found to affect effective cells of the immune system (natural killer cells) and biological response modifiers. The present study was designed to determine whether hyperthermia enhances the anti-tumor activity of Lip-MP in vivo.Methods: Before animal tests, DOTAP: Cholesterol-DNA complex was prepared. Animal tumor models were established by injecting Meth A fibrosarcoma (Meth A) cells or Colon Tumor 26 (CT 26) cells into the tight of BALB/c mice. Then mice were randomly divided into 6 groups, and treated with Saline control, Lip-null, heating, Lip-MP, Lip-null plus heating and Lip-MP plus heating every four days for four times. Tumor size was determined every 4 days by direct measurement with external calipers. A week after all treatment, one half of models were sacrificed to preparate for histologic slice, the other half existed for the observation of suvival time.Results: We suggest that Lip-MP plus HT apparently increase the number of apoptotic tumor cells compared with Lip-MP or HT alone. Mean tumor volumes of the group treated with Lip-MP plus HT dramatically smaller than the contrastive group. Especially, the combination treatment eliminated part of established tumor in two different tumor models and significantly prolonged survival time of tumor-bearing mice. Histological analyses of tumors revealed that compared with Lip-MP or HT alone, combination treatment noticeably increased necrosis and apoptosis.Conclusion: This study suggests that the combined treatment with Lip-MP plus HT may augment the induction of apoptosis in cancer cells in vivo, and that the augmented anti-tumor activity in vivo may result from synergistic induction of apoptosis in cancer cells. The present findings may be of importance to the further exploration of the potential application of this combined approach in the treatment of cancer. Moreover, this also support that Lip-MP will be applied in the clinic as a new agent with adjuvant HT for cancer.