This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bullard, D. E. Articles by Bigner, D. D. Search for Related Content PubMed PubMed Citation Articles by Bullard, D. E. Articles by Bigner, D. D.

Comparison of Intravenous versus Intracarotid Therapy with 1,3-Bis(2-chloroethyl)-1-nitrosourea in a Rat Brain Tumor Model¹

Departments of Surgery (Neurosurgery) and Pathology (Neuropathology), Duke University Medical Center, Durham, North Carolina 27710

Currently numerous clinical trials are in progress utilizing intracarotid (i.c.) 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) for the treatment of malignant gliomas based upon the proposed focal nature of these tumors and the assumption that the i.c. route delivers higher levels of drug to the tumor. To date, however, increased efficacy in an animal model has not been clearly demonstrated for the i.c. delivery of BCNU. We have evaluated the dose-response curve for the i.v. and i.c. administration of BCNU in a commonly utilized experimental brain tumor model, the 9L rat gliosarcoma. An initial toxicity trial utilizing the i.p. 10% lethal dose (LD₁₀) of BCNU by the i.v. and i.c. routes failed to demonstrate any significance in toxicity between the two routes. Tumor-bearing animals were then treated on Day 15–16 after tumor inoculations with 1, 10, 25, 50, 75, and 100% of the LD₁₀ dose by either the i.v. or the i.c. route. Both i.v. and i.c. BCNU gave maximum survival increases at 75–100% LD₁₀ doses, and there was no therapeutic advantage seen from i.c. delivery. However, at 50% of the LD₁₀ dose (6.65 mg/kg), triplicate experiments demonstrated that the i.c. but not the i.v. dose maintained maximum efficacy equivalent to 100% of the LD₁₀ given either i.v. or i.c. When the dose was reduced to 25% of the LD₁₀ dose (3.33 mg/kg), two of three experiments showed efficacy of the i.c. delivery of this lower drug dosage to be equivalent to 100% of the LD₁₀ given i.v. or i.c. The i.v. dosage resulted in a significant reduction in survival in all three trials. At 10% of the LD₁₀ dose (1.30 mg/kg), neither the i.v. nor the i.c. administration retained equivalent efficacy to 100% of the LD₁₀. However, in one of two trials, the i.c. groups had statistically better survival than controls, while in neither experiment was any advantage over controls seen in the i.v. treated groups. At 1% of the LD₁₀ dose, neither the i.v. nor the i.c. route demonstrated any therapeutic efficacy. From our data, the advantage of the i.c. delivery of BCNU in the intracranial 9L rat gliosarcoma appears to be in the fact that significantly lower dosages than those given i.v. may be utilized to achieve equivalent survival with potentially less systemic toxicity.

¹ This work was supported by Grant NS 20023 and TIA Award 1 K070080-01 (D. E. B.) from NINCDS and Grants CA 11909 and CA 32672 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Box 3128, Duke University Medical Center, Durham, NC 27710.

Received 3/26/85. Revised 7/ 9/85. Accepted 8/ 5/85.

This article has been cited by other articles:

				B. Geoerger, C.-B. Tang, A. Cesano, S. Visonneau, S. Marwaha, K. D. Judy, L. N. Sutton, D. Santoli, and P. C. Phillips Antitumor activity of a human cytotoxic T-cell line (TALL-104) in brain tumor xenografts Neuro-oncol, April 1, 2000; 2(2): 103 - 113. [Abstract] [PDF]