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Development of an Animal Brain Tumor Model and Its Response to Therapy with 1,3-Bis(2-chloroethyl)-1-nitrosourea¹

Howard C. Naffziger Laboratories for Neurosurgical Research, Department of Neurological Surgery, Cancer Research Institute [M. B., T. H., O. G., C. B. W., R. D., J. E.], and Department of Pathology [S. L. N.], University of California, San Francisco, California 94122

A chemically induced rat glioma, carried in cell culture, was transplanted to the brain of CDF rats. The tumor thrived in cell culture, producing a typical malignant astrocytoma when implanted in rat brain. Survival of tumor-bearing rats varied in different experimental groups, but the range of survival within each experimental group was within acceptable limits.

The rat glioma in cell culture grew progressively through three phases, namely, exponential, stationary, and a variable phase, limited by space and medium. The cell-cycle time of the glioma in vivo was 20 hr, the growth fraction was 0.35 to 0.46, the observed doubling time was 72 hr, and the cell-loss factor was 0.42. These data, along with the chronology of the cell-cycle phases, enhance the usefulness of this system as a model for brain tumor chemotherapy.

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) significantly increased the survival time of rats bearing intracerebral gliomas. A dose of BCNU approximating 40% of the 10% lethal dose, when given 9 and 16 days after tumor implantation, produced an increased life-span of 38%. A dose of BCNU equivalent to 80% of the 10% lethal dose given on Days 9 and 16 produced an increased life-span of 84%. When BCNU was withheld until the 16th and 23rd days, a significant increase in survival time was still evident.

The advantages of this animal model for brain tumor chemotherapy are that (a) the transplanted tumor is of glial origin, (b) the tumor take of the model has been 100%, (c) the mean survival of animals is approximately 30 days, permitting the start of a treatment schedule after the tumor has grown to significant size, and (d) the rat is suitable for various routes of therapy.

¹ This work was supported in part by the American Cancer Society, California Division, by USPHS Clinical Cancer Research Center Grant 5 PO CA 11067, by NIH Cancer Center Grant CA 112 49-01, and by a gift from Phi Beta Psi Sorority.

² Present address: Department of Neurosurgery, University of Tokyo, Tokyo, Japan.

³ Present address: Department of Neurosurgery, Hacettepe University Medical Center, Ankara, Turkey.

⁴ Al Holman Undergraduate Fellow (1970 to 1971), United Commercial Benevolent Foundation, Inc.

⁵ Al Holman Undergraduate Fellow (1969 to 1970), United Commercial Benevolent Foundation, Inc.

Received 4/17/72. Accepted 1/26/73.

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