Recent advances in the molecular genetics of malignant gliomas disclose targets for antitumor agent perillyl alcohol.

Tumors of glial origin such as glioblastoma multiforme (GBM) comprise the majority of human brain tumors. Despite advances in surgery, radiation, and chemotherapy, the prognosis for patients with malignant glioma has not improved, emphasizing the need for a search for new chemotherapeutic drugs. Deregulated p21-Ras function, as a result of mutation, overexpression, or growth factor-induced overactivation, contributes to the growth of GBM. The monoterpene perillyl alcohol (POH) has preventive and therapeutic effects in a wide variety of preclinical tumor models and is currently under phase I and phase II clinical trials. As inhibition of posttranslational isoprenylation of Ras, a family of proteins that are involved in signal transduction is among the drug-related activities observed in this compound; POH may be a potential chemotherapeutic agent for GBM. Intranasal delivery is a practical and noninvasive approach that allows therapeutic agents that do not cross the blood-brain barrier to enter the central nervous system, reducing unwanted systemic side effects. This article describes the effect of intranasal delivery of POH in a patient with relapsed GBM.

[1]  G. Finocchiaro,et al.  Gene therapy of experimental brain tumors using neural progenitor cells , 2000, Nature Medicine.

[2]  A. Guha,et al.  Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects , 1999, Oncogene.

[3]  K. Kaibuchi,et al.  The post-translational processing of ras p21 is critical for its stimulation of mitogen-activated protein kinase. , 1993, The Journal of biological chemistry.

[4]  D. DeMets,et al.  Phase II trial of perillyl alcohol (NSC 641066) administered daily in patients with metastatic androgen independent prostate cancer , 2003, Investigational New Drugs.

[5]  L. Parada,et al.  The Molecular and Genetic Basis of Neurological Tumours , 2002, Nature Reviews Cancer.

[6]  J. Shapiro.  Genetics of nervous system tumors. , 2001, Hematology/oncology clinics of North America.

[7]  S. Litwin,et al.  Phase I pharmacokinetic trial of perillyl alcohol (NSC 641066) in patients with refractory solid malignancies. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[8]  W. Shi,et al.  Induction of cytostasis in mammary carcinoma cells treated with the anticancer agent perillyl alcohol. , 2002, Carcinogenesis.

[9]  H. Mo,et al.  Studies of the Isoprenoid-Mediated Inhibition of Mevalonate Synthesis Applied to Cancer Chemotherapy and Chemoprevention , 2004, Experimental biology and medicine.

[10]  Ramsis Benjamin,et al.  Classification of Glioblastoma Multiforme in Adults by Molecular Genetics , 2003, Cancer journal.

[11]  M. Israel,et al.  Platelet-derived growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways in glioblastoma cells: evidence that the novel PDGF-C and PDGF-D ligands may play a role in the development of brain tumors. , 2002, Cancer research.

[12]  T. Jang,et al.  Association of increased phosphatidylinositol 3-kinase signaling with increased invasiveness and gelatinase activity in malignant gliomas. , 2001, Journal of neurosurgery.

[13]  V. Levin.  Chemotherapy for brain tumors of astrocytic and oligodendroglial lineage: the past decade and where we are heading. , 1999, Neuro-oncology.

[14]  S. Clark,et al.  Perillyl alcohol selectively induces G0/G1 arrest and apoptosis in Bcr/Abl-transformed myeloid cell lines , 1999, Leukemia.

[15]  J. McKinzie,et al.  Induction of the apoptosis-promoting protein Bak by perillyl alcohol in pancreatic ductal adenocarcinoma relative to untransformed ductal epithelial cells. , 1997, Carcinogenesis.

[16]  J. Berlin,et al.  Phase II trial of perillyl alcohol in patients with metastatic colorectal cancer , 2002, International journal of gastrointestinal cancer.

[17]  M N Gould,et al.  Structure-activity relationships among monoterpene inhibitors of protein isoprenylation and cell proliferation. , 1994, Biochemical pharmacology.

[18]  J. Goldstein,et al.  Regulation of the mevalonate pathway , 1990, Nature.

[19]  C. James,et al.  PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. , 2001, Journal of the National Cancer Institute.

[20]  M. Kris,et al.  A phase I trial of perillyl alcohol in patients with advanced solid tumors , 2003, Cancer Chemotherapy and Pharmacology.

[21]  M. Bozza,et al.  Effects of perillyl alcohol in glial C6 cell line in vitro and anti-metastatic activity in chorioallantoic membrane model. , 2002, International journal of molecular medicine.

[22]  T. Y. Shih,et al.  Metabolic turnover of human c-rasH p21 protein of EJ bladder carcinoma and its normal cellular and viral homologs , 1984, Molecular and cellular biology.

[23]  D. Louis,et al.  Subsets of Glioblastoma Multiforme Defined by Molecular Genetic Analysis , 1993, Brain pathology.

[24]  S. Clark,et al.  Antileukemia activity of perillyl alcohol (POH): uncoupling apoptosis from G0/G1 arrest suggests that the primary effect of POH on Bcr/Abl-transformed cells is to induce growth arrest , 2002, Leukemia.

[25]  D. Coppola,et al.  The Phosphoinositide 3-OH Kinase/AKT2 Pathway as a Critical Target for Farnesyltransferase Inhibitor-Induced Apoptosis , 2000, Molecular and Cellular Biology.

[26]  Y. Yarden.  The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. , 2001, European journal of cancer.

[27]  A. Guha,et al.  Isotype-specific Ras.GTP-levels predict the efficacy of farnesyl transferase inhibitors against human astrocytomas regardless of Ras mutational status. , 2001, Cancer research.

[28]  A. Pawson,et al.  Proliferation of human malignant astrocytomas is dependent on Ras activation , 1997, Oncogene.

[29]  J. Belanger.  Perillyl alcohol: applications in oncology. , 1998, Alternative medicine review : a journal of clinical therapeutic.

[30]  S. Wadler,et al.  A phase II trial of daily perillyl alcohol in patients with advanced ovarian cancer: Eastern Cooperative Oncology Group Study E2E96. , 2002, Gynecologic oncology.

[31]  J. Karp,et al.  Current status of clinical trials of farnesyltransferase inhibitors , 2001, Current opinion in oncology.

[32]  M. Ellis,et al.  Activation of the transforming growth factor beta signaling pathway and induction of cytostasis and apoptosis in mammary carcinomas treated with the anticancer agent perillyl alcohol. , 1999, Cancer research.

[33]  Li Zhong,et al.  Anti-leukemia effect of perillyl alcohol in Bcr/Abl-transformed cells indirectly inhibits signaling through Mek in a Ras- and Raf-independent fashion. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[34]  V. Steele,et al.  Chemoprevention of colon carcinogenesis by dietary perillyl alcohol. , 1997, Cancer research.

[35]  R. Jirtle,et al.  Induction of apoptosis in liver tumors by the monoterpene perillyl alcohol. , 1995, Cancer research.

[36]  D. Gutmann,et al.  Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas. , 2001, Cancer research.

[37]  C. Gattass,et al.  Perillyl alcohol induces apoptosis in human glioblastoma multiforme cells. , 2005, Oncology reports.

[38]  S. Howard,et al.  Perillyl Alcohol as a Radio-/Chemosensitizer in Malignant Glioma* , 2003, Journal of Biological Chemistry.

[39]  Catherine L Nutt,et al.  Genetic Alterations of Phosphoinositide 3‐kinase Subunit Genes in Human Glioblastomas , 2004, Brain pathology.