Nicotine dependence is a chronic mental illness that is characterized by a negative affective state upon tobacco smoking cessation and relapse after periods of abstinence. It has been hypothesized that cessation of nicotine administration results in the activation of brain corticotropin-releasing factor (CRF) systems that leads to the negative affective state of withdrawal. The aim of our experiments was to investigate the role of brain CRF systems in the deficit in brain reward function associated with the cessation of nicotine administration in rats. The intracranial self-stimulation procedure was used to assess to negative affective aspects of nicotine withdrawal as this procedure can provide a quantitative measure of emotional distress in rats. In the first experiment, mecamylamine induced a dose-dependent elevation in brain reward thresholds in nicotine-treated rats. In the follow-up experiment, it was shown that pretreatment with the corticotropin-receptor antagonist D-Phe CRF prevents the elevations in brain reward thresholds associated with precipitated nicotine withdrawal. In the third experiment, the effect of D-Phe CRF on the elevations in brain reward thresholds associated with spontaneous nicotine withdrawal was investigated. Administration of D-Phe CRF 6 h after the explantation of the nicotine pumps, did not result in a lowering of the brain reward thresholds. These findings indicate that antagonism of CRF receptors prevents, but not reverses, the deficit in brain associated with nicotine withdrawal. These data provide support for the hypothesis that a hyperactivity of brain CRF systems may at least partly mediate the initiation of the negative affective aspects of nicotine withdrawal. Neuropsychopharmacology (2007) 32, 955-963.

The prognosis of patients with malignant glioma remains extremely poor despite surgery and improvement in radio and chemo therapies. Unfortunately few drugs cross the blood-brain barrier. Therapeutic treatment with chemotherapy agents, e.g., temozolomide, 1,3 bis (2-chloroethinyl)-1 nitrosurea carmustine wafers or tipifarnib have not significantly improved patient survival. Mifepristone has been found to provide significant palliative benefit to both mice with various types of malignancies and also humans with a wide variety of advanced cancers no longer or unresponsive to chemotherapy. The hypothesized mechanism of action is that tumor cells either directly secrete or cause gamma delta T cells in the tumor microenvironment to secrete a similar immunomodulatory protein as in normal pregnancies which inhibits natural killer (NK) cell cytotoxicity and causes a shift from thymic helper (TH)1 cytokines which stimulate cellular immune responses to TH2cytokines which evoke a humoral response. This protein is called the progesterone induced blocking factor (PIBF). The hypothesis suggests that also similar to pregnancy, progesterone or a P-like substance secreted by the tumor up-regulates PIBF response. Mifepristone has been found to down-regulate PIBF expression from human leukemia cell lines. Whether this is the precise mechanism of action or not, the progesterone receptor antagonist seems to inhibit tumor growth and provide extended and better quality of life. The objective of the present study was to determine if mifepristone may cross the blood brain barrier and provide a palliative benefit to patients with stage IV glioblastoma multiforme. A 43 year old male with a large glioblastoma multiforme grade IV malignant brain tumor arising originally from the temporal lobe with metastases to the spinal cord was told that he was no longer a candidate for anymore chemo or radiation therapy. He was advised that death should occur within 2 months. Indeed 2 months later death was considered imminent. He slept most of the day and was unable to converse. He was completely paralyzed from the neck down and his hands were in a clenched position. After 2 weeks of taking 200mg/day of mifepristone he became alert and was able to carry out intelligent conversations. He was now able to open his hand. He remained alert for 3 months, but paralysis had spread making swallowing difficult. He could not longer ingest the mifepristone. He died 2 weeks later. This case proves that mifepristone can cross the blood brain barrier and provide palliative benefits for grade IV glioblastoma multiforme. It is well tolerated with minimal or no side effects at this dosage. In view of the paucity of effective therapy for this type of cancer, mifepristone should be given consideration for treatment earlier than this extremely advanced stage. Citation Format: Jerome H. Check, Carrie Wilson, Diane Check. Evidence that mifepristone, a progesterone receptor antagonist, can cross the blood brain barrier and provide palliative benefits for glioblastoma multiforme grade IV. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 485. doi:10.1158/1538-7445.AM2013-485

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These cases helped influence the US Food and Drug Association in granting an investigator-initiated investigational new drug study on advanced non-small cell lung cancer.