8/11/97

A group of doctors from across the country has designed an innovative and new experimental drug treatment for malignant brain tumors. By directly applying a modified toxin of the common Pseudomonas bacterium to a tumor, the doctors have been able to destroy brain tumor cancer cells in experimental models in a matter of hours.

Dr. Robert W. Rand of the John Wayne Cancer Institute (JWCI), Dr. Raj Puri of the Food and Drug Administration (FDA), and Drs. Robert Kreitman and Ira Pastan of the National Cancer Institute (NCI) have combined to develop this new therapy. Currently approved by the John Wayne Cancer Institute and the FDA Institutional Review Boards (IRB) to conduct a Phase I Clinical Trial, Dr. Rand is currently seeking candidates for this experimental treatment. Eligible individuals must have recurrent malignant brain tumors that have failed to respond to standard therapy such as surgery, radiation and/or chemotherapy. Patients should be between the ages of 18 and 70 and not be impaired neurologically.

If you have any questions or comments, please e-mail us at medi@MediciMed.com or call Dr. Rand at (888) 625-3431.

Preclinical Development of a Recombinant Toxin Containing Circularly Permuted Interleukin 4 and Truncated Pseudomonas Exotoxin for Therapy of Malignant Astrocytoma¹

Raj K. Puri,² Dave S. Hoon, Pamela Leland, Phil Snoy, Robert W. Rand, Ira Pastan, and Robert J. Kreitman

Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies [R.K.P., P.L.], and Division of Veterinary Services [P.S.], Center for Biologics Evaluation and Research, Food and Drug Administration, NIH, Bethesda, Maryland 20892; Saint John’s Hospital and Health Center, John Wayne Cancer Institute, Division of Molecular and Cellular Immunology and Neuro-Oncology, Santa Monica California [D.S.H., R.W.R.]; and Laboratory of Molecular Biology, Division of Cancer Biology, Diagnosis and Centers, National Cancer Institute, NIH, Bethesda, Maryland 20892 [I.P., R.J.K.]

ABSTRACT

Effective treatment is lacking for malignant glioblastoma/astrocytoma. We have identified interleukin-4 receptors (IL-4R) on human malignant astrocytoma. We demonstrate that 16 of 21 surgical samples of high-grade astrocytoma and glioblastoma but not normal brain tissues expressed IL-4R as assessed by reverse transcriptase PCR. We further demonstrate that human malignant astrocytoma cell lines express high-affinity IL-4R. Using a chimeric protein composed of circularly permuted IL-4 and a truncated form of Pseudomonas exotoxin A, we observed that this toxin (IL4(38-37)-PE38KDEL) is highly cytotoxic to IL-4R-bearing glioblastoma cells. Compared with a previously reported IL4-PE chimeric protein (IL-PE4E) IL4(38-37)-PE38KDEL bound with higher affinity and was 3-30 fold more cytotoxic to glioblastoma cell lines. Upon intrathecal administration in monkeys, high cerebrospinal fluid IL4(38-37)-PE38KDEL levels were not detectable in the serum of any monkey studied. When IL4(38-37)-PE38KDEL was injected into the right frontal cortex of rats, localized necrosis was observed at 1000-ng/ml doses but not at £ 100-ng/ml doses. We conclude that by localized administration, nontoxic levels of IL4(38-37)-PE38KDEL can be achieved, which may have significant cytotoxic activity against malignant astrocytoma.

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