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Tumor Targeting by Covalent Conjugation of a Natural Fatty Acid to Paclitaxel
Ist Teil von
Clinical cancer research, 2001-10, Vol.7 (10), p.3229-3238
Ort / Verlag
Philadelphia, PA: American Association for Cancer Research
Erscheinungsjahr
2001
Quelle
EZB-FREE-00999 freely available EZB journals
Beschreibungen/Notizen
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 n m 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 or120 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.