1.Ras pathway activation in gliomas: a strategic target for intranasal administration of perillyl alcohol.
da Fonseca CO1, Linden R, Futuro D, Gattass CR, Quirico-Santos T. Arch Immunol Ther Exp (Warsz). 2008 Jul-Aug;56(4):267-76. doi: 10.1007/s00005-008-0027-0. Epub 2008 Jul 29.
INTRODUCTION: Targeted therapy directed at specific molecular alterations is already creating a shift in the treatment of cancer patients. Malignant gliomas commonly overexpress the oncogenes EGFR and PDGFR and contain mutations and deletions of the tumor suppressor genes PTEN and TP53. Some of these alterations lead to activation of the P13K/Akt and Ras/MAPK pathways, which provide targets for therapy. Perillyl alcohol (POH), the isoprenoid of greatest clinical interest, was initially considered to inhibit farnesyl protein transferase. Follow-up studies revealed that POH suppresses the synthesis of small G proteins, including Ras. Intranasal delivery allows drugs that do not cross the blood-brain barrier to enter the central nervous system. Moreover, it eliminates the need for systemic delivery, thereby reducing unwanted systemic side effects.
2.Gas chromatographic-mass spectrometric analysis of perillyl alcohol and metabolites in plasma.
Zhang Z1, Chen H, Chan KK, Budd T, Ganapathi R. J Chromatogr B Biomed Sci Appl. 1999 May 14;728(1):85-95.
Perillyl alcohol (POH), a metabolite of d-limonene and a component of the lavender oil, is currently in Phase I clinical trials both as a chemopreventative and chemotherapeutic agent. In vivo, POH is metabolized to less active perillic acid (PA) and cis- and trans-dihydroperillic acids [DHPA, 4-(1'-methylethenyl)-cyclohexane-1-carboxylic acid]. Previous pharmacokinetic studies using a GC-MS method detected POH metabolites but not POH itself; thus these studies lacked information on the parent drug. The present report describes a sensitive GC-MS method for the quantitation of POH and metabolites using stable-isotopically labeled internal standards. The residue obtained from CH2Cl2 extraction of a plasma sample was silylated. The products were separated on a capillary column and analyzed by an ion-trap GC-MS using NH3 chemical ionization. POH-d3 was used as the internal standard for POH while 13C-PA-d2 was used as the internal standards for the metabolites.
3.A novel temozolomide-perillyl alcohol conjugate exhibits superior activity against breast cancer cells in vitro and intracranial triple-negative tumor growth in vivo.
Chen TC1, Cho HY, Wang W, Barath M, Sharma N, Hofman FM, Schönthal AH. Mol Cancer Ther. 2014 May;13(5):1181-93. doi: 10.1158/1535-7163.MCT-13-0882. Epub 2014 Mar 12.
There is no effective therapy for breast cancer that has spread to the brain. A major roadblock is the blood-brain barrier (BBB), which prevents the usual breast cancer drugs from effectively reaching intracranial metastases. The alkylating agent temozolomide (TMZ) is able to penetrate the BBB and has become the gold standard for chemotherapeutic treatment of glioblastoma. However, when it was tested in clinical trials for activity against brain metastases of breast cancer, the results were mixed and ranged from "encouraging activity" to "no objective responses." In an effort to generate an agent with greater activity against intracranial breast metastases, we synthesized a TMZ analog where the natural product perillyl alcohol (POH) was covalently linked to TMZ's amide functionality. The resulting novel compound, called TMZ-POH (T-P), displayed greatly increased anticancer activity in a variety of breast cancer cell lines, inclusive of TMZ-resistant ones.
4.Perillyl alcohol induces apoptosis in human glioblastoma multiforme cells.
Fernandes J1, da Fonseca CO, Teixeira A, Gattass CR. Oncol Rep. 2005 May;13(5):943-7.
Standard treatment of glioblastoma multiforme consisting of surgical resection, radiation and/or chemotherapy is rarely curative, emphasizing the need for new chemotherapeutic drugs. The monoterpene perillyl alcohol (POH) has preventive and therapeutic effects in a wide variety of pre-clinical tumor models and is currently under phase I and II clinical trials. In the present study, we analyzed its effect on human glioblastoma cell lines (U87 and A172) and a primary cell culture derived from a human glioblastoma tumor specimen (GBM-1). Using MTT, we showed that POH inhibits the viability of glioblastomas in a concentration-dependent way. Glioblastoma cell lines treated with POH showed morphological alterations characteristic of apoptosis. Analysis of cell cycle and quantification of DNA fragmentation, in cells stained with propidium iodide (PI), confirmed the apoptotic effect of POH on glioblastomas. These data support the potential usefulness of perillyl alcohol as an effective chemotherapeutic agent for patients with recurrent glioblastoma multiforme.