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Neoplasms	1

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Tubulin	1

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.

Clinical Cancer Research

Tumor Targeting by Covalent Conjugation of a Natural Fatty Acid to Paclitaxel

Author: Philip A. Witman ; Forrest H. Anthony ; Matthews O. Bradley ; Prabu Devanesan ; Madhavi C. Chander ; Nigel L. Webb ; S. Hemamalini ; Lifeng He ; Charles S. Swindell ; Sharyn D. Baker ; Susan Band Horwitz

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.

Clinical Cancer Research

Disposition of docosahexaenoic acid-paclitaxel, a novel taxane, in blood: In vitro and clinical pharmacokinetic studies

Author: Charles S. Swindell ; Jaap Verweij ; Alex Sparreboom ; Yelena Zabelina ; Ross C. Donehower ; Desiree M. van Zomeren ; Antonio C. Wolff ; Sharyn D. Baker ; Gregory L. McIntire

Purpose: Docosahexaenoic acid-paclitaxel is as an inert prodrug composed of the natural fatty acid DHA covalently linked to the C2′-position of paclitaxel (M. O. Bradley et al ., Clin. Cancer Res., 7: 3229–3238, 2001). Here, we examined the role of protein binding as a determinant of the pharmacokinetic behavior of DHA-paclitaxel. Experimental Design: The blood distribution of DHA-paclitaxel was studied in vitro using equilibrium dialysis and in 23 cancer patients receiving the drug as a 2-h i.v. infusion (dose, 200-1100 mg/m 2 ). Results: In vitro , DHA-paclitaxel was found to bind extensively to human plasma (99.6 ± 0.057%). The binding was concentration independent ( P = 0.63), indicating a nonspecific, nonsaturable process. The fraction of unbound paclitaxel increased from 0.052 ± 0.0018 to 0.055 ± 0.0036 (relative increase, 6.25%; P = 0.011) with an increase in DHA-paclitaxel concentration (0–1000 μg/ml), suggesting weakly competitive drug displacement from protein-binding sites. The mean (± SD) area under the curve of unbound paclitaxel increased nonlinearly with dose from 0.089 ± 0.029 μg·h/ml (at 660 mg/m 2 ) to 0.624 ± 0.216 μg·h/ml (at 1100 mg/m 2 ), and was associated with the dose-limiting neutropenia in a maximum-effect model (R 2 = 0.624). A comparative analysis indicates that exposure to Cremophor EL and unbound paclitaxel after DHA-paclitaxel (at 1100 mg/m 2 ) is similar to that achieved with paclitaxel on clinically relevant dose schedules. Conclusions: Extensive binding to plasma proteins may explain, in part, the unique pharmacokinetic profile of DHA-paclitaxel described previously with a small volume of distribution (∼4 liters) and slow systemic clearance (∼0.11 liters/h).

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Pipeline

Pipeline Snapshot as of 05 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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