DHA Conjugate Increases Paclitaxel Uptake by Tumor Cells

DHA Conjugate Increases Paclitaxel Uptake by Tumor Cells

NEW YORK—A novel taxane/fatty acid conjugate designed to increase
taxane activity in tumor cells and decrease toxicity has shown promising
results in a phase I trial of patients with solid tumors. Ross Donehower,
MD, professor of oncology and medicine, Sidney Kimmel Comprehensive Cancer
Center at Johns Hopkins University, presented the findings at the
Chemotherapy Foundation Symposium XIX (abstract 73).

DHA-paclitaxel (Taxoprexin, Protarga, Inc) is a combination of
paclitaxel conjugated at the active site to docosahexaenoic acid (DHA), an
essential fatty acid, "which serves, in this concept, as a target
vector for tumor cells," Dr. Donehower said.

Tumor cells actively take up and utilize fatty acids, both as membrane
precursors and as energy sources, to a greater extent than do noncancer
cells. "It’s felt that perhaps this would be a way in which taxanes
could be introduced more effectively into the cell," he said.

After preclinical studies provided evidence that DHA-paclitaxel did
increase paclitaxel uptake by tumor cells, a phase I trial was initiated at
Johns Hopkins. The study enrolled 24 patients with a variety of solid
tumors. All 13 men and 11 women had received prior chemotherapy. "We
did eliminate patients who had anything more than mild peripheral
neuropathy," Dr. Donehower said, "because of the desire to
ascertain whether or not DHA-paclitaxel does cause peripheral

The drug was given in a 2-hour infusion every 21 days. Doses escalated
from 200 mg/m² to 1,100 mg/m². At an evaluation after the first two cycles
of treatment, Dr. Donehower reported, "roughly half the patients were
stable or in one case responding." After four cycles of therapy, 6
patients continued to have stable disease. Overall, 10 of 21 evaluable
patients achieved stabilization, and 1 had a complete response.

The major and dose-limiting toxicity was neutropenia, Dr. Donehower
reported. Of the nine patients who received 1,100 mg/m² DHA-paclitaxel,
seven had grade 3-4 febrile neutropenia, he noted. At the next lower dose of
880 mg/m², grade 4 neutropenia was seen in three of the six patients, but
only one of these patients became febrile. Nonhematologic toxicity was
generally mild.

Pharmacokinetic analyses showed that the volume of distribution of DHA-paclitaxel
was "about 1/50th that of paclitaxel," Dr. Donehower reported,
"and it circulates in this nontoxic state." The clearance rate, he
added, is slow, approximately 1/300th that of paclitaxel. The half-life of
the paclitaxel derived from DHA-paclitaxel was about 80 hours, compared with
8 to 10 hours for Taxol.


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