Certain natural
fatty acids are taken up avidly by
tumors for use as biochemical precursors and energy sources. We tested in mice the hypothesis that the conjugation of
docosahexaenoic acid (DHA), a natural
fatty acid, and an anticancer
drug would create a new chemical entity that would target
tumors and reduce toxicity to normal tissues. We synthesized
DHA-paclitaxel, a 2'-O-acyl conjugate of the natural
fatty acid DHA and
paclitaxel. The data show that the conjugate possesses increased antitumor activity in mice when compared with
paclitaxel. For example,
paclitaxel at its optimum dose (20 mg/kg) caused neither complete nor partial regressions in any of 10 mice in a Madison 109 (M109) s.c. lung
tumor model, whereas
DHA-paclitaxel caused complete regressions that were sustained for 60 days in 4 of 10 mice at 60 mg/kg, 9 of 10 mice at 90 mg/kg, and 10 of 10 mice at the optimum dose of 120 mg/kg. The
drug seems to be inactive as a
cytotoxic agent until metabolized by cells to an active form. The conjugate is less toxic than
paclitaxel, so that 4.4-fold higher molar doses can be delivered to mice.
DHA-paclitaxel in rats has a 74-fold lower volume of distribution and a 94-fold lower clearance rate than
paclitaxel, suggesting that the
drug is primarily confined to the plasma compartment.
DHA-paclitaxel is stable in plasma, and high concentrations are maintained in mouse plasma for long times.
Tumor targeting of the conjugate was demonstrated by pharmacokinetic studies in M109
tumor-bearing mice, indicating an area under the
drug concentration-time curve of
DHA-paclitaxel in
tumors that is 8-fold higher than
paclitaxel at equimolar doses and 57-fold higher at equitoxic doses. At equimolar doses, the
tumor area under the
drug concentration-time curve of
paclitaxel derived from i.v.
DHA-paclitaxel is 6-fold higher than for
paclitaxel derived from i.v.
paclitaxel. Even at 2 weeks
after treatment, 700 nM
paclitaxel remains in the
tumors after
DHA-paclitaxel treatment. Low concentrations of
DHA-paclitaxel or
paclitaxel derived from
DHA-paclitaxel accumulate in gastrocnemius muscle; which may be related to the finding that
paclitaxel at 20 mg/kg caused hind limb
paralysis in nude mice, whereas
DHA-paclitaxel caused none, even at doses of 90 or 120 mg/kg. The dose-limiting toxicity in rats is myelosuppression, and, as in the mouse, little
DHA-paclitaxel is converted to
paclitaxel in plasma. Because
DHA-paclitaxel remains in
tumors for long times at high concentrations and is slowly converted to cytotoxic
paclitaxel,
DHA-paclitaxel may kill those slowly cycling or
residual tumor cells that eventually come into cycle.