Sensitivity of 5-fluorouracil-resistant cancer cells to adenovirus suicide gene therapy

Abstract

A promising approach for cancer gene therapy is the combination of adenovirus vectors (AdV) with the suicide gene cytosine deaminase and uracil phosphoribosyl transferase (CDHUPRT). While such vectors have been tested in tumor cell lines and xenograft models, it is not clear how these therapeutic vectors would perform in primary human tumors. We, thus, examined the effect of the combination of a recombinant adenovirus expressing the CDHUPRT (AdCU) with 5-fluorocytosine (5-FC) on primary cancer cells isolated from the ascites or pleural fluids of patients with metastatic cancers. In such models, we have found a direct correlation between the patients' response to 5-FU and the response shown by the cancer cells in vitro, confirming the clinical relevance of this methodology. Our findings demonstrated that this combination was able to kill primary tumor cells, including those that had developed resistance to 5-FU. Furthermore, while proliferating cells were more susceptible to 5-FU, the combination was effective in both rapid and slow proliferating samples. Our study demonstrated that this gene therapy approach could provide an effective therapeutic option for cancers and is not affected by acquired 5-FU resistance. Also of importance is the effectiveness of this gene therapy approach on slower proliferating cells that is typical of the majority of cancers in vivo. This suggests a greater likelihood that it will be effective in a clinical setting.

Prodrug Gene Therapy for Cancer Mediated by Mesenchymal Stem/Stromal Cells Engineered to Express Yeast Cytosinedeaminase::Uracilphos phoribosyltransferase

“…The yCD::UPRT-AT-MSCs suicide system was shown to be effective against 5-FUresistant human primary cancer cells [29]. Our results support this finding by showing that C6 glioblastoma cells enriched for 5-FU resistant cells did not differ in sensitivity to ThSC-mediated killing in vitro [13].…”

Suicide genes for cancer therapy

“…Recently, Richard and colleagues demonstrated the efficacy of this combination against slowly proliferating cells and primary tumours which have developed 5-FU resistance (Richard et al, 2006).…”

Apoptotic Induction with Bifunctional E.coli Cytosine Deaminase-Uracil Phosphoribosyltransferase Mediated Suicide Gene Therapy is Synergized by Curcumin Treatment In vitro

“…The extensive use of E. coli cytosine deaminase (CD) in the context of adenoviral vectors is well known [5]. The CD enzyme converts prodrug 5-FC to 5-flurouracil (5-FU), which kills the cells by triggering apoptosis [5], but the use of 5-FC/CD system is limited owing to its inefficient bystander effect to the neighboring cells in malignant tumors [6]. The new generation bifunctional gene consisting of E. coli cytosine deaminase and uracil phosphoribosyl transferase (CD-UPRT) were reported to be more effective, where the uracil phosphoribosyl transferase further converts 5-FU into more cytotoxic 5-flurouracilmonophosphate (5-FUMP), which is further converted to 5-flurodeoxyuracilmonophosphate (5-FdUMP) and 5-flurouraciltriphosphate (5-FUTP) and thereby increased the cytotoxicity [7].…”