Targeted toxin therapy for malignant astrocytoma.
The poor prognosis associated with malignant astrocytoma has led investigators to seek new, innovative methods of treatment. Targeted toxins represent a unique form of therapy that has two components, a carrier molecule with high specificity for tumor-associated antigens and a potent protein toxin. These compounds are extremely cytotoxic to malignant astrocytoma cell lines in vitro. Animal studies have shown prolongation of survival and complete tumor regression when targeted toxins were administered by a variety of routes. The promising results seen in vivo have formed the basis for proceeding with clinical trials in humans with leptomeningeal neoplasia and malignant brain tumors, in which these agents are administered intrathecally or directly into tumor, respectively. To date, in these clinical trials, targeted toxins have been delivered safely without significant neurological toxicity, and cytological analysis of cerebrospinal fluid and radiological findings have shown evidence of a therapeutic response. These studies have confirmed the existence of a therapeutic window between normal brain tissue and malignant cells that can be exploited with targeted therapy directed against the transferrin receptor. The successful delivery of targeted toxins directly into malignant brain tumors has established this route of administration as practical and feasible. Identification of other receptors that are preferentially expressed on brain tumors, such as the interleukin-4 receptor, has resulted in the creation of a fusion protein against this receptor that contains a modified toxin from the bacteria Pseudomonas aeruginosa. This chimeric fusion toxin is currently under investigation in a Phase I clinical trial with patients with recurrent malignant astrocytoma, and other targeted toxins are under development for the treatment of these uniformly fatal tumors. Owing to these recent advances in targeted toxin therapy for malignant primary brain tumors, a review of the development of these agents for practicing neurosurgeons seems timely.
Hall
W A
WA
Department of Neurosurgery, University of Minnesota School of Medicine, Minneapolis, USA.
D000818:Animals; D001254:Astrocytoma / Q000188:drug therapy* / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002986:Clinical Trials as Topic; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000922:Immunotoxins