Effect and Mechanism of Mitomycin C Combined with Recombinant Adeno-Associated Virus Type II against Glioma

Abstract

The effect of chemotherapy drug Mitomycin C (MMC) in combination with recombinant adeno-associated virus II (rAAV2) in cancer therapy was investigated, and the mechanism of MMC affecting rAAV2’s bioactivity was also studied. The combination effect was evaluated by the level of GFP and TNF expression in a human glioma cell line, and the mechanism of MMC effects on rAAV mediated gene expression was investigated by AAV transduction related signal molecules. C57 and BALB/c nude mice were injected with rAAV-EGFP or rAAV-TNF alone, or mixed with MMC, to evaluate the effect of MMC on AAV-mediated gene expression and tumor suppression. MMC was shown to improve the infection activity of rAAV2 both in vitro and in vivo. Enhancement was found to be independent of initial rAAV2 receptor binding stage or subsequent second-strand synthesis of target DNA, but was related to cell cycle retardation followed by blocked genome degradation. In vivo injection of MMC combined with rAAV2 into the tumors of the animals resulted in significant suppression of tumor growth. It was thus demonstrated for the first time that MMC could enhance the expression level of the target gene mediated by rAAV2. The combination of rAAV2 and MMC may be a promising strategy in cancer therapy.

Glioma stem cells and their roles within the hypoxic tumor microenvironment

“…The quinone mitomycin C (MMC) is activated under hypoxic conditions in tumor cells 238 . In glioma, MMC combined with recombinant adeno-associated virus II resulted in reduced tumor growth in vivo 239 . MMC-mediated GBM cell death was also increased when cells were pretreated with the DT-diaphorase inducer, dimethyl fumarate 240 .…”

Adeno-associated virus (AAV) vectors in cancer gene therapy

“…Other AAV-delivered immunostimulatory transgenes that have elicited anti-tumor effects include secondary lymphoid tissue chemokine (SLC), delivered preventatively and therapeutically by AAV2 to a Hepal-6 mouse liver cancer tumor model [133]; Nk4, delivered by AAV2 to a metastatic Lewis lung carcinoma (LLC) mouse model [134]; the cytokine LIGHT, delivered by AAV2 to a TC-1 mouse cervical cancer model [135]; the granulocyte-macrophage colony stimulation factor (GM-CSF) cytokine, delivered by AAV1 to a 9L tumor model [136]; and TNF-α, delivered by AAV2 to a U251 human glioma xenograft mouse model [137]. …”