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Cancer Resources > Cancer News > 2004 > March
Modified vitamin B12 shuttles lethal cargo to tumors
Megan Rauscher
Last Updated: 2004-03-30 15:20:16 -0400 (Reuters Health)
ORLANDO, Florida (Reuters Health) - Nitrosylcobalamin (NO-Cbl), a modified version of cobalamin containing nitric oxide (NO), has significant antitumor activity in mice. Moreover, tumors that are resistant to killing by recombinant TRAIL/Apo2L (TNF-related apoptosis-inducing ligand) become sensitive to TRAIL/Apo2L apoptosis when pretreated with NO-Cbl.
"Not only is NO-Cbl in and of itself an effective frontline chemotherapeutic, it enhances the effectiveness of other chemotherapeutic agents," Dr. Joseph A. Bauer, the scientist who synthesized NO-Cbl, told Reuters Health. Dr. Bauer, of the Cleveland Clinic Foundation in Ohio, presented his team's latest research on NO-Cbl at the 95th annual meeting of the American Association for Cancer Research.
Armed with the knowledge that tumor cells selectively take up large amounts of vitamin B12 and produce significantly more of the B12 receptor than normal cells, Dr. Bauer modified vitamin B12 to include a NO bond. "NO-Cbl is picked up by the receptor [and] brought inside the tumor cell where it releases lethal amounts of NO, killing the cancer cell," Dr. Bauer explained.
Because NO-Cbl releases only under acidic conditions inside the cancer cell, there is minimal toxicity. "We have not seen any systemic effects in any of the animal studies," Dr. Bauer said.
The antitumor growth effects of NO-Cbl alone and in combination with anticancer drugs have been confirmed in over 60 different cancer cell lines and in several studies in mice, Dr. Bauer said.
At the AACR on Tuesday, he reported that, in culture, NO-Cbl pretreatment sensitized TRAIL/Apo2L-resistant melanoma cells to growth inhibition by TRAIL/Apo2L.
In mice bearing human malignant melanoma xenografts, the combination of NO-Cbl and TRAIL/Apo2L led to significant tumor regression. Administration of NO-Cbl 24 hours before TRAIL/Apo2L was "most effective, producing nearly complete tumor regression," Dr. Bauer said.
Mechanistic studies show that NO-Cbl not only upregulates the TRAIL/Apo2L death pathway, it also inhibits the NFkB pathway that promotes tumor cell survival. "The ability of NO-Cbl to inhibit survival pathways is very important," Dr. Bauer said, "because cell survival mechanisms limit the antitumor effects of frontline chemotherapeutics."
Dr. Bauer and colleagues will seek regulatory approval for initial human clinical trials this summer. "The first clinical trials will look at NO-Cbl 's antitumor activity in ovarian cancer," he explained, "because currently there are no effective treatments to target ovarian cancer."
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