FHIT gene replacement therapy using a chimeric adenovirus shows promise for leukemia

10-24-2006

"Expression of the FHIT protein is lost or reduced in most solid tumors and a significant fraction of hematopoietic malignancies. Adenovirus 5 (Ad5) virus or adeno-associated viral vectors have been used to study the tumor suppressor function of FHIT in solid tumors, but these tools have not been effective in leukemias. We have generated a chimeric FHIT-containing adenovirus composed of Ad5 and the group B adenovirus called F35 with which we have been able to efficiently infect hematopoietic cells," scientists in the United States report.

"Infection efficiency of Ad5/F35-FHIT and Ad5/F35-GFP viruses was tested in leukemia cell lines that lacked FHIT expression, and biological effects of successful infection were assessed," said Flavia Pichiorri and colleagues at Ohio State University. "An acute myelogenous leukemia, a chronic myelogenous leukemia, and four acute lymphoblastic leukemia human cell lines were examined as well as two EBV-transformed B lymphoblastoid cell lines that expressed endogenous FHIT."

The researchers reported, "Two of four acute lymphoblastic leukemia cell lines, Jurkat and MV4;11, which were efficiently infected with Ad5/F35-FHIT, underwent growth suppression and massive induction of apoptosis without apparent activation of caspase-8 or caspase-2 and late activation of caspase-3. Treatment of infected cells with caspase-9 and caspase-3 inhibitors partially blocked FHIT-induced apoptosis. The two remaining infected acute lymphoblastic leukemia cell lines, Molt-3 and RS4;11, were apparently unaffected."

"Restoration of FHIT expression in the chronic myelogenous leukemia K562 cell line and the acute myelogenous leukemia KG1a cell line also induced apoptosis but at later time points than seen in the acute lymphoblastic leukemia Jurkat and MV4;11 cell lines," stated the investigators. "IV injection of Ad5/F35-FHIT-infected Jurkat cells resulted in abrogation of tumorigenicity in the NOD/SCID xenogeneic engraftment model. FHIT restoration in some FHIT-deficient leukemia cells induces both antiproliferative and pro-apoptotic effects involving the intrinsic caspase apoptotic pathway."

Pichiorri and coauthors published their study in Clinical Cancer Research (Preclinical assessment of FHIT gene replacement therapy in human leukemia using a chimeric adenovirus, Ad5/F35. Clin Cancer Res, 2006;12(11 Part 1):3494-3501).

For more information, contact Flavia Pichiorri, Ohio State University Comprehensive Cancer Center, Wiseman Hall, Room 441, 410 West 12th Avenue, Columbus, OH 43210, USA. pichiorri.1@osu.edu.

Keywords: Columbus, Ohio, United States, Leukemia Vaccine, Vaccine Development, DNA Vaccine, Cancer Vaccine, Adenoviral Vector, Adenovirus, Vector Development, Chronic Myelogenous Leukemia, Chronic Myeloid Leukemia, Hematology, Oncology, Gene Therapy, Proteomics, Virology.

This article was prepared by Biotech Business Week editors from staff and other reports. Copyright 2006, Biotech Business Week via NewsRx.com.