Sensitivity of 5-fluorouracil-resistant cancer cells to adenovirus suicide gene therapy.
A promising approach for cancer gene therapy is the combination of adenovirus vectors (AdV) with the suicide gene cytosine deaminase and uracil phosphoribosyl transferase (CDColon, two colonsUPRT). 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 CDColon, two colonsUPRT (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.
Richard
C
C
Regional Cancer Program, Thunder Bay Regional Health Sciences Centre, Thunder Bay, Ontario, Canada.
Duivenvoorden
W
W
Bourbeau
D
D
Massie
B
B
Roa
W
W
Yau
J
J
Th'ng
J
J
D000256:Adenoviridae / Q000235:genetics; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology*; D015316:Genetic Therapy; D006801:Humans; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil