Inhibition of oral cancer cell growth by adenovirusMnSOD plus BCNU treatment.
We hypothesized that inhibitors of peroxide removal, such as BCNU, an indirect inhibitor of glutathione peroxidase (GPx), and 3-amino-1,2,4-triazole (AT), a direct inhibitor of catalase (CAT), should cause toxicity to cancer cells after manganese superoxide dismutase (MnSOD) overexpression due to elevated peroxide levels. In vitro, hamster cheek pouch carcinoma cells (HCPC-1) and human oral squamous carcinoma cells (SCC-25) were infected with various combinations of adenovirus containing MnSOD cDNA (AdMnSOD). Cells were then treated with or without BCNU and assayed for viability using Annexin/PI staining and flow cytometry. In AdMnSOD plus BCNU-treated SCC-25 and HCPC-1 cells, a 30-60% decrease in cell viability was observed compared to BCNU alone. In vivo, HCPC-1 and SCC-25 xenografts were allowed to grow to approximately 70 mm(3) and 10(9) plaque forming units (pfu) of AdMnSOD were injected directly into the tumors. Two days later, 15 or 30 mg/kg BCNU was injected intratumorally. Tumor growth was greatly inhibited (4- to 20-fold) by this combined treatment, as well as increasing animal survival. Tumor volume could be decreased further by giving multiple doses of AdMnSOD or inhibiting catalase activity with AT. These results suggest that, by using these combination therapies, a significant decrease in tumor mass can be achieved.
Darby Weydert
Christine J
CJ
Free Radical and Radiation Biology Program, Department of Radiation Oncology, Roy J. and Lucille A. Carver College of Medicine and Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
Smith
Benjamin B
BB
Xu
Linjing
L
Kregel
Kevin C
KC
Ritchie
Justine M
JM
Davis
Charles S
CS
Oberley
Larry W
LW
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002330:Carmustine / Q000494:pharmacology*; D002374:Catalase / Q000037:antagonists & inhibitors; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D003131:Combined Modality Therapy; D006224:Cricetinae; D015316:Genetic Therapy; D006801:Humans; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000975:Antioxidants; D002374:Catalase; D013482:Superoxide Dismutase; D002330:Carmustine