Paclitaxel disposition in plasma and central nervous systems of humans and rats with brain tumors

Michael J. Glantz, Hak Choy, Christine M. Kearns, Pam C. Mills, Lars U. Wahlberg, Eleanor G. Zuhowski, Paul Calabresi, Merrill J. Egorin

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

Background: Paclitaxel (Taxol) has been shown to sensitize some malignant cells to the effects of radiation. A number of clinical protocols, combining paclitaxel with radiation therapy, have been designed to exploit this phenomenon. The radiation-potentiating effect of paclitaxel is likely dependent on the ability of the drug to penetrate the tissue being radiated. Paclitaxel is known to have limited access to the central nervous system (CNS) of rats and mice, but is ability to penetrate malignant tissue in the CNS is inadequately documented. Purpose: Our purpose was to examine the concentrations of paclitaxel in the cerebrospinal fluid (CSF) of patients with CNS malignancies and in normal and malignant tissues from the brains of Fischer rats bearing the C6 rat glioma and then to compare those paclitaxel concentrations with concomitant paclitaxel concentrations in the plasma of those same patients and animals. Methods: Four patients were treated with 3- hour infusions of paclitaxel at doses between 90 and 200 mg/m2. Plasma and CSF were sampled at 0.33, 1.5, 3.25, 5, 6, and 24 hours after initiation of the paclitaxel infusion. Four Fischer rats had 20 000 C6 glioma cells stereotactically implanted into their right frontal lobes; 28 days later, they were given 3-hour infusions of paclitaxel at 10 mg/kg. Plasma was sampled during the paclitaxel infusion. At the completion of the infusion, rats were killed, and portions of their normal and malignant CNS tissues were removed for histologic assessment. Concentrations of paclitaxel in plasma, CSF, and brain tissue were determined with high-pressure liquid chromatography. Results: Plasma pharmacokinetics of paclitaxel in patients with brain tumors were comparable to those previously described in patients with other malignancies. Paclitaxel could be measured in CSF of all patients, but concentrations were very low. Peak paclitaxel concentrations in CSF ranged between 5 and 83 nM and occurred between 3.25 and 5 hours after initiation of the paclitaxel infusion. Peak paclitaxel concentrations in CSF were between 0.12% and 8.3% of those present in concomitant plasma samples. Paclitaxel was not detectable in the normal or malignant CNS tissue of any rat, despite the fact that plasma concentrations of paclitaxel at the time of tissue acquisition ranged from 0.62 to 153 μM. Conclusions: Paclitaxel has only limited access to the CSF of patients with CNS malignancies and to normal and malignant CNS tissues of rats bearing brain tumors. Implications: The utility of combining paclitaxel with radiation therapy to treat CNS malignancies should be considered in light of the documented limited access of paclitaxel to the CNS.

Original languageEnglish (US)
Pages (from-to)1077-1081
Number of pages5
JournalJournal of the National Cancer Institute
Volume87
Issue number14
StatePublished - Jul 19 1995

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Brain Tumor
Neurology
Cerebrospinal fluid
Paclitaxel
Brain Neoplasms
Rats
Tumors
Brain
Plasma
Central Nervous System
Plasmas
Tissue
Fluid
Bearings (structural)
Radiation Therapy
Cerebrospinal Fluid
Radiotherapy
Nerve Tissue
High pressure liquid chromatography
Human

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Physiology (medical)
  • Radiology Nuclear Medicine and imaging

Cite this

Glantz, M. J., Choy, H., Kearns, C. M., Mills, P. C., Wahlberg, L. U., Zuhowski, E. G., ... Egorin, M. J. (1995). Paclitaxel disposition in plasma and central nervous systems of humans and rats with brain tumors. Journal of the National Cancer Institute, 87(14), 1077-1081.

Paclitaxel disposition in plasma and central nervous systems of humans and rats with brain tumors. / Glantz, Michael J.; Choy, Hak; Kearns, Christine M.; Mills, Pam C.; Wahlberg, Lars U.; Zuhowski, Eleanor G.; Calabresi, Paul; Egorin, Merrill J.

In: Journal of the National Cancer Institute, Vol. 87, No. 14, 19.07.1995, p. 1077-1081.

Research output: Contribution to journalArticle

Glantz, MJ, Choy, H, Kearns, CM, Mills, PC, Wahlberg, LU, Zuhowski, EG, Calabresi, P & Egorin, MJ 1995, 'Paclitaxel disposition in plasma and central nervous systems of humans and rats with brain tumors', Journal of the National Cancer Institute, vol. 87, no. 14, pp. 1077-1081.
Glantz MJ, Choy H, Kearns CM, Mills PC, Wahlberg LU, Zuhowski EG et al. Paclitaxel disposition in plasma and central nervous systems of humans and rats with brain tumors. Journal of the National Cancer Institute. 1995 Jul 19;87(14):1077-1081.
Glantz, Michael J. ; Choy, Hak ; Kearns, Christine M. ; Mills, Pam C. ; Wahlberg, Lars U. ; Zuhowski, Eleanor G. ; Calabresi, Paul ; Egorin, Merrill J. / Paclitaxel disposition in plasma and central nervous systems of humans and rats with brain tumors. In: Journal of the National Cancer Institute. 1995 ; Vol. 87, No. 14. pp. 1077-1081.
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abstract = "Background: Paclitaxel (Taxol) has been shown to sensitize some malignant cells to the effects of radiation. A number of clinical protocols, combining paclitaxel with radiation therapy, have been designed to exploit this phenomenon. The radiation-potentiating effect of paclitaxel is likely dependent on the ability of the drug to penetrate the tissue being radiated. Paclitaxel is known to have limited access to the central nervous system (CNS) of rats and mice, but is ability to penetrate malignant tissue in the CNS is inadequately documented. Purpose: Our purpose was to examine the concentrations of paclitaxel in the cerebrospinal fluid (CSF) of patients with CNS malignancies and in normal and malignant tissues from the brains of Fischer rats bearing the C6 rat glioma and then to compare those paclitaxel concentrations with concomitant paclitaxel concentrations in the plasma of those same patients and animals. Methods: Four patients were treated with 3- hour infusions of paclitaxel at doses between 90 and 200 mg/m2. Plasma and CSF were sampled at 0.33, 1.5, 3.25, 5, 6, and 24 hours after initiation of the paclitaxel infusion. Four Fischer rats had 20 000 C6 glioma cells stereotactically implanted into their right frontal lobes; 28 days later, they were given 3-hour infusions of paclitaxel at 10 mg/kg. Plasma was sampled during the paclitaxel infusion. At the completion of the infusion, rats were killed, and portions of their normal and malignant CNS tissues were removed for histologic assessment. Concentrations of paclitaxel in plasma, CSF, and brain tissue were determined with high-pressure liquid chromatography. Results: Plasma pharmacokinetics of paclitaxel in patients with brain tumors were comparable to those previously described in patients with other malignancies. Paclitaxel could be measured in CSF of all patients, but concentrations were very low. Peak paclitaxel concentrations in CSF ranged between 5 and 83 nM and occurred between 3.25 and 5 hours after initiation of the paclitaxel infusion. Peak paclitaxel concentrations in CSF were between 0.12{\%} and 8.3{\%} of those present in concomitant plasma samples. Paclitaxel was not detectable in the normal or malignant CNS tissue of any rat, despite the fact that plasma concentrations of paclitaxel at the time of tissue acquisition ranged from 0.62 to 153 μM. Conclusions: Paclitaxel has only limited access to the CSF of patients with CNS malignancies and to normal and malignant CNS tissues of rats bearing brain tumors. Implications: The utility of combining paclitaxel with radiation therapy to treat CNS malignancies should be considered in light of the documented limited access of paclitaxel to the CNS.",
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N2 - Background: Paclitaxel (Taxol) has been shown to sensitize some malignant cells to the effects of radiation. A number of clinical protocols, combining paclitaxel with radiation therapy, have been designed to exploit this phenomenon. The radiation-potentiating effect of paclitaxel is likely dependent on the ability of the drug to penetrate the tissue being radiated. Paclitaxel is known to have limited access to the central nervous system (CNS) of rats and mice, but is ability to penetrate malignant tissue in the CNS is inadequately documented. Purpose: Our purpose was to examine the concentrations of paclitaxel in the cerebrospinal fluid (CSF) of patients with CNS malignancies and in normal and malignant tissues from the brains of Fischer rats bearing the C6 rat glioma and then to compare those paclitaxel concentrations with concomitant paclitaxel concentrations in the plasma of those same patients and animals. Methods: Four patients were treated with 3- hour infusions of paclitaxel at doses between 90 and 200 mg/m2. Plasma and CSF were sampled at 0.33, 1.5, 3.25, 5, 6, and 24 hours after initiation of the paclitaxel infusion. Four Fischer rats had 20 000 C6 glioma cells stereotactically implanted into their right frontal lobes; 28 days later, they were given 3-hour infusions of paclitaxel at 10 mg/kg. Plasma was sampled during the paclitaxel infusion. At the completion of the infusion, rats were killed, and portions of their normal and malignant CNS tissues were removed for histologic assessment. Concentrations of paclitaxel in plasma, CSF, and brain tissue were determined with high-pressure liquid chromatography. Results: Plasma pharmacokinetics of paclitaxel in patients with brain tumors were comparable to those previously described in patients with other malignancies. Paclitaxel could be measured in CSF of all patients, but concentrations were very low. Peak paclitaxel concentrations in CSF ranged between 5 and 83 nM and occurred between 3.25 and 5 hours after initiation of the paclitaxel infusion. Peak paclitaxel concentrations in CSF were between 0.12% and 8.3% of those present in concomitant plasma samples. Paclitaxel was not detectable in the normal or malignant CNS tissue of any rat, despite the fact that plasma concentrations of paclitaxel at the time of tissue acquisition ranged from 0.62 to 153 μM. Conclusions: Paclitaxel has only limited access to the CSF of patients with CNS malignancies and to normal and malignant CNS tissues of rats bearing brain tumors. Implications: The utility of combining paclitaxel with radiation therapy to treat CNS malignancies should be considered in light of the documented limited access of paclitaxel to the CNS.

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