Safety and efficacy of convection-enhanced delivery of gemcitabine or carboplatin in a malignant glioma model in rats

Jeffrey W. Degen, Stuart Walbridge, Alexander O. Vortmeyer, Edward H. Oldfield, Russell R. Lonser

Research output: Contribution to journalArticle

103 Citations (Scopus)

Abstract

Object. Convection-enhanced delivery (CED) can be used safely to perfuse regions of the central nervous system (CNS) with therapeutic agents in a manner that bypasses the blood-brain barrier (BBB). These features make CED a potentially ideal method for the distribution of potent chemotherapeutic agents with certain pharmacokinetic properties to tumors of the CNS. To determine the safety and efficacy of the CED of two chemotherapeutic agents (with properties ideal for this method of delivery) into the CNS, the authors perfused naive rats and those harboring 9L gliomas with carboplatin or gemcitabine. Methods. Dose-escalation toxicity studies were performed by perfusing the striatum (10 μl, 24 rats) and brainstem (10 μl, 16 rats) of naive rats with carboplatin (0.1, 1, and 10 mg/ml) or gemcitabine (0.4, 4, and 40 mg/ml) via CED. Efficacy trials involved the intracranial implantation of 9L tumor cells in 20 Fischer 344 rats. The tumor and surrounding regions were perfused with 40 μl of saline (control group, four rats), 1 mg/ml of carboplatin (four rats), or 4 mg/ml of gemcitabine (four rats) 7 days after implantation. Eight rats harboring the 9L glioma were treated with the systemic administration of 60 mg/kg of carboplatin (four rats) or 150 mg/kg of gemcitabine (four rats) 7 days postimplantation. Clinical, gross, and histological analyses were used to determine toxicity and efficacy. Toxicity occurred in rats that had received only the highest dose of the CED of carboplatin or gemcitabine. Among rats with 9L gliomas, all control and systemically treated animals died within 26 days of tumor implantation. Long-term survival (120 days) and eradication of the tumor occurred in both CED-treated groups (75% of rats in the carboplatin group and 50% of rats in the gemcitabine group). Furthermore, animals harboring the 9L glioma and treated with intratumoral CED of carboplatin or gemcitabine survived significantly longer than controls treated with intratumoral saline (p < 0.01) or systemic chemotherapy (p < 0.01). Conclusions. The perfusion of sensitive regions of the rat brain can be accomplished without toxicity by using therapeutic concentrations of carboplatin or gemcitabine. In addition, CED of carboplatin or gemcitabine to tumors in this glioma model is safe and has potent antitumor effects. These findings indicate that similar treatment paradigms may be useful in the treatment of glial neoplasms in humans.

Original languageEnglish (US)
Pages (from-to)893-898
Number of pages6
JournalJournal of neurosurgery
Volume99
Issue number5
DOIs
StatePublished - Nov 2003

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gemcitabine
Convection
Carboplatin
Glioma
Safety
Neoplasms
Central Nervous System

Keywords

  • Carboplatin
  • Chemotherapy
  • Convection-enhanced delivery
  • Gemcitabine
  • Glioma
  • Rat

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

Cite this

Safety and efficacy of convection-enhanced delivery of gemcitabine or carboplatin in a malignant glioma model in rats. / Degen, Jeffrey W.; Walbridge, Stuart; Vortmeyer, Alexander O.; Oldfield, Edward H.; Lonser, Russell R.

In: Journal of neurosurgery, Vol. 99, No. 5, 11.2003, p. 893-898.

Research output: Contribution to journalArticle

Degen, Jeffrey W. ; Walbridge, Stuart ; Vortmeyer, Alexander O. ; Oldfield, Edward H. ; Lonser, Russell R. / Safety and efficacy of convection-enhanced delivery of gemcitabine or carboplatin in a malignant glioma model in rats. In: Journal of neurosurgery. 2003 ; Vol. 99, No. 5. pp. 893-898.
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abstract = "Object. Convection-enhanced delivery (CED) can be used safely to perfuse regions of the central nervous system (CNS) with therapeutic agents in a manner that bypasses the blood-brain barrier (BBB). These features make CED a potentially ideal method for the distribution of potent chemotherapeutic agents with certain pharmacokinetic properties to tumors of the CNS. To determine the safety and efficacy of the CED of two chemotherapeutic agents (with properties ideal for this method of delivery) into the CNS, the authors perfused naive rats and those harboring 9L gliomas with carboplatin or gemcitabine. Methods. Dose-escalation toxicity studies were performed by perfusing the striatum (10 μl, 24 rats) and brainstem (10 μl, 16 rats) of naive rats with carboplatin (0.1, 1, and 10 mg/ml) or gemcitabine (0.4, 4, and 40 mg/ml) via CED. Efficacy trials involved the intracranial implantation of 9L tumor cells in 20 Fischer 344 rats. The tumor and surrounding regions were perfused with 40 μl of saline (control group, four rats), 1 mg/ml of carboplatin (four rats), or 4 mg/ml of gemcitabine (four rats) 7 days after implantation. Eight rats harboring the 9L glioma were treated with the systemic administration of 60 mg/kg of carboplatin (four rats) or 150 mg/kg of gemcitabine (four rats) 7 days postimplantation. Clinical, gross, and histological analyses were used to determine toxicity and efficacy. Toxicity occurred in rats that had received only the highest dose of the CED of carboplatin or gemcitabine. Among rats with 9L gliomas, all control and systemically treated animals died within 26 days of tumor implantation. Long-term survival (120 days) and eradication of the tumor occurred in both CED-treated groups (75{\%} of rats in the carboplatin group and 50{\%} of rats in the gemcitabine group). Furthermore, animals harboring the 9L glioma and treated with intratumoral CED of carboplatin or gemcitabine survived significantly longer than controls treated with intratumoral saline (p < 0.01) or systemic chemotherapy (p < 0.01). Conclusions. The perfusion of sensitive regions of the rat brain can be accomplished without toxicity by using therapeutic concentrations of carboplatin or gemcitabine. In addition, CED of carboplatin or gemcitabine to tumors in this glioma model is safe and has potent antitumor effects. These findings indicate that similar treatment paradigms may be useful in the treatment of glial neoplasms in humans.",
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T1 - Safety and efficacy of convection-enhanced delivery of gemcitabine or carboplatin in a malignant glioma model in rats

AU - Degen, Jeffrey W.

AU - Walbridge, Stuart

AU - Vortmeyer, Alexander O.

AU - Oldfield, Edward H.

AU - Lonser, Russell R.

PY - 2003/11

Y1 - 2003/11

N2 - Object. Convection-enhanced delivery (CED) can be used safely to perfuse regions of the central nervous system (CNS) with therapeutic agents in a manner that bypasses the blood-brain barrier (BBB). These features make CED a potentially ideal method for the distribution of potent chemotherapeutic agents with certain pharmacokinetic properties to tumors of the CNS. To determine the safety and efficacy of the CED of two chemotherapeutic agents (with properties ideal for this method of delivery) into the CNS, the authors perfused naive rats and those harboring 9L gliomas with carboplatin or gemcitabine. Methods. Dose-escalation toxicity studies were performed by perfusing the striatum (10 μl, 24 rats) and brainstem (10 μl, 16 rats) of naive rats with carboplatin (0.1, 1, and 10 mg/ml) or gemcitabine (0.4, 4, and 40 mg/ml) via CED. Efficacy trials involved the intracranial implantation of 9L tumor cells in 20 Fischer 344 rats. The tumor and surrounding regions were perfused with 40 μl of saline (control group, four rats), 1 mg/ml of carboplatin (four rats), or 4 mg/ml of gemcitabine (four rats) 7 days after implantation. Eight rats harboring the 9L glioma were treated with the systemic administration of 60 mg/kg of carboplatin (four rats) or 150 mg/kg of gemcitabine (four rats) 7 days postimplantation. Clinical, gross, and histological analyses were used to determine toxicity and efficacy. Toxicity occurred in rats that had received only the highest dose of the CED of carboplatin or gemcitabine. Among rats with 9L gliomas, all control and systemically treated animals died within 26 days of tumor implantation. Long-term survival (120 days) and eradication of the tumor occurred in both CED-treated groups (75% of rats in the carboplatin group and 50% of rats in the gemcitabine group). Furthermore, animals harboring the 9L glioma and treated with intratumoral CED of carboplatin or gemcitabine survived significantly longer than controls treated with intratumoral saline (p < 0.01) or systemic chemotherapy (p < 0.01). Conclusions. The perfusion of sensitive regions of the rat brain can be accomplished without toxicity by using therapeutic concentrations of carboplatin or gemcitabine. In addition, CED of carboplatin or gemcitabine to tumors in this glioma model is safe and has potent antitumor effects. These findings indicate that similar treatment paradigms may be useful in the treatment of glial neoplasms in humans.

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KW - Carboplatin

KW - Chemotherapy

KW - Convection-enhanced delivery

KW - Gemcitabine

KW - Glioma

KW - Rat

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