2000 Fiscal Year Final Research Report Summary
Adenovirus-mediated human topoisomerase IIα gene transfer increases the sensitivity of etoposide-resistant cancer cells
| Project/Area Number |
10670147
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Nippon Medical School |
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Principal Investigator |
ASANO Takeshi Nippon Medical School, Depaernt of Pediatrics, Associate Professor, 医学部, 助教授 (70277490)
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| Project Period (FY) |
1998 – 2000
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| Keywords | topoisomerasde IIα / adenovirus / gene transfer / etoposide / drug resistant / leukemia / breast cancer |
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| Research Abstract |
Cellular resistance to chemotherapeutic agents is attributable to several mechanisms, including alteration of topoisomerase IIα gene expression. Our previous studies have shown that transient transfection with a vector containing either Drosophila or human topoisomerase IIα gene into drug-resistant tumor cells enhanced their drug sensitivity. Furthermore, we constructed a recombinant adenovirus, Ad-hTopoIIα, containing the human topoisomerase IIα gene that was able to selectively increase etoposide sensitivity in drug-resistant tumor cells. We also examined Ad-hTopoIIα for therapeutic efficacy in vitro using additional etoposide-resistant cell lines, including a mouse breast cancer cell line and a human leukemia cell line. The etoposide-resistant mouse breast cancer cell line FvP, which is derived from FM3A, and etoposide-resistant human breast cancer cell line, MDA-VP from MDA-P cells showed increased sensitivity to etoposide as well as increased expression of human Topoisomerase IIα mRNA, but this was not seen in FM3A and MDA-P cells. On the other hand, the etoposide-resistant human leukemia cell line K562/MX2 and the parental cell line K562/P did not show enhanced sensitivity against etoposide or an increase in human Topoisomerase IIα mRNA. Using a recombinant adenovirus containing β-galactosidase gene (Ad-β-gal), K562 cells were not transducted by the recombinant adenovirus, while both etoposide-sensitive FM3A cells and etoposide resistant FvP cells were transducted by recombinant adenovirus. Ad-hTOP2α and etopside treatment showed reduced inoculated tumor weight in the mice. We concluded that a recombinant adenovirus containing the human Topoisomerase IIαa gene might be a powerful tool for overcoming drug resistance in breast cancer cells, but not that in leukemia cells.
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