This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The leptomeninges are an increasingly common site of recurrence for various malignancies, in part because of the limited penetration of most systemically administered anticancer drugs across the blood-CSF barrier. Direct intra-CSF administration of anticancer drugs, either into the ventricles through an intraventricular reservoir (Ommaya or Rickham) or via lumbar puncture, is one approach to circumvent the issue of a pharmacologic sanctuary. However, only a limited number of anticancer agents can be safely administered directly into the CSF, limiting the effectiveness of this form of regional chemotherapy. In recent years, the development of a unique nonhuman primate model(1) has made possible testing of several novel intra-CSF agents including diaziquone(2), mafosfamide(3), 6-mercaptopurine(4), and topotecan(5). Gemcitabine, a relatively new antineoplastic agent with activity against both solid tumors and leukemias has recently been studied in this model and appears to be a promising potential alternative therapy for patients with neoplastic meningitis. Gemcitabine has documented preclinical and clinical activity against a wide variety of malignancies. It is FDA-approved for use as first-line treatment for pancreatic carcinoma (5). It is also active in advanced non small-cell lung cancer, small-cell lung cancer, breast carcinoma, bladder carcinoma, ovarian cancer(7,8), head and neck cancer (9), and testicular carcinomas (6-8). In addition, it has activity against leukemias and non-Hodgkin's lymphoma(13,14). Therefore, this phase 1 trial will evaluate the safety and pharmacokinetics of intrathecal gemcitabine in patients with neoplastic meningitis.
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