ArticleLiterature Review

The antitumor action of cannabinoids on glioma tumorigenesis

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Abstract

Cannabinoids are a class of chemical compounds with a wide spectrum of pharmacological effects, mediated by two specific plasma membrane receptors (CB1 and CB2). Recently, CB1 and CB2 expression levels have been detected in human tumors, including those of brain. Cannabinoids-endocannabinoids exert anti-inflammatory, anti-proliferative, anti-invasive, anti-metastatic and pro-apoptotic effects in different cancer types, both in vitro and in vivo in animal models, after local or systemic administration. We present the available experimental and clinical data, to date, regarding the antitumor action of cannabinoids on the tumorigenesis of gliomas.

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... Although the anti-cancer effect of cannabinoids has been intensively studied in cell cultures (test-tube studies) and in animals with tumours, no firm conclusions about their clinical use are yet possible. It has been confirmed repeatedly that THC and various other cannabinoids binding to CB 1 and CB 2 cannabinoid receptors, and CBD acting through different mechanisms, can promote cancer cell death, or retard or prevent the growth of cancer cells of various types, including lung, prostate, pancreas, colon and brain cancer (Dando et al., 2013;De Petrocellis et al., 2013;Haustein, Ramer, Linnebacher, Manda, & Hinz, 2014;Macpherson, Armstrong, Criddle, & Wright, 2014;Zogopoulos, Korkolopoulou, Patsouris, & Theocharis, 2015). The cannabinoids also reduce the ability of cancer cells to invade surrounding normal tissues and to metastasize (i.e., give rise to colonies of cancer cells in many different tissues at a distance from the original cancer site). ...
... At such high concentrations, the side effects of drugs acting via CB 1 receptors would be intolerable to patients. Therefore current research on anti-cancer actions is focused principally on CBD and on synthetic cannabinoids acting exclusively through CB 2 receptors (Fowler, 2015;Massi, Solinas, Cinquina, & Parolaro, 2013;Zogopoulos et al., 2015). The early findings are encouraging, but they have not yet led to the development of effective treatment for cancer in humans. ...
Article
Cannabis sativa has long been used for medicinal purposes. To improve safety and efficacy, compounds from C. sativa were purified or synthesized and named under an umbrella group as cannabinoids. Currently, several cannabinoids may be prescribed in Canada for a variety of indications such as nausea and pain. More recently, an increasing number of reports suggest other salutary effects associated with endogenous cannabinoid signaling including cardioprotection. The therapeutic potential of cannabinoids is therefore extended; however, evidence is limited and mechanisms remain unclear. In addition, the use of cannabinoids clinically has been hindered due to pronounced psychoactive side effects. This review provides an overview on the endocannabinoid system, including known physiological roles, and conditions in which cannabinoid receptor signaling has been implicated.
... Both receptors are expressed by normal glial cells and by gliomas, and the activation of these receptors has been found to regulate cellular differentiation, function, and cell viability. 17,18 In vitro studies suggest a possible therapeutic role for cannabinoids via the inhibition of tumor proliferation and angiogenesis, induction of tumor cell death, and inhibition of invasiveness and stem cell-like properties of GBM. [19][20][21] While the neuroprotective effects of marijuana have been postulated, [22][23][24] chronic habitual recreational cannabis is associated with potential adverse side effects 25 ; in the brain, these include structural changes and functional impairments that may impact cognition. ...
Article
Background: Glioma is a devastating primary tumor of the central nervous system with difficult-to-manage symptoms. Cannabis products have been postulated to potentially benefit glioma patients. Recent state legalization allowed investigators an opportunity to study glioma patients' adoption of medical marijuana (MM). Objective: Our goals were to: (1) determine the prevalence of marijuana use, both through physician recommendation and self-medication, and (2) evaluate its perceived risks and benefits in glioma patients. Design: Self-report data were collected and descriptive analyses were conducted. Setting/Subjects: Participants were adult, English-speaking patients undergoing treatment for primary non-recurrent malignant glioma in neuro-oncology clinics at an NCI-designated Comprehensive Cancer Center. Measurements: The survey on MM was adapted from previous research and included questions on knowledge and attitudes toward MM; use, frequency, type, and sourcing of MM; and reasons for use of MM and perceived symptom relief among users. Results: A total of 73 patients were surveyed. The majority of participants were aware that MM was legal in the state, and most reported learning of this through the media. Over 70% of participants reported having considered using MM, and a third reported using marijuana products after their diagnosis. Most received recommendations from friends/family rather than a medical provider, and only half of the users had obtained a physician's recommendation. Users generally reported benefits. Conclusions: With the increasing national conversation that accompanies legalization, glioma patients are pursuing marijuana for the treatment for their symptoms. More research and education is needed to bring health care providers into the conversation.
... In fact, a pilot clinical analysis in patients with glioblastoma multiforme noted the ability of Δ 9 -THC, intratumourally administered, to reduce tumour growth and at the same time maintain a safe profile [255]. Currently, two clinical trials are being carried out to determine the efficacy and safety of Δ 9 -THC/CBD in combination with temozolomide, in these tumours (NCT03529448, NCT01812603) [256]. In addition, another clinical study is now being conducted with CBD (in combination with chemotherapy) in the treatment of glioblastoma, myeloma and gastrointestinal carcinomas (NCT03607643) [257]. ...
Article
Cannabinoid receptors, endocannabinoids and the enzymes responsible for their biosynthesis and degradation constitute the endocannabinoid system. In recent decades, the endocannabinoid system has attracted considerable interest as a potential therapeutic target in numerous pathological conditions. Its involvement in several physiological processes is well known, such as in energy balance, appetite stimulation, blood pressure, pain modulation, embryogenesis, nausea and vomiting control, memory, learning and immune response, among others, as well as in pathological conditions where it exerts a protective role in the development of certain disorders. As a result, it has been reported that changes in endocannabinoid levels may be related to neurological diseases such as Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and multiple sclerosis, as well as anorexia and irritable bowel syndrome. Alterations in the endocannabinoid system have also been associated with cancer, affecting the growth, migration and invasion of some tumours. Cannabinoids have been tested in several cancer types, including brain, breast and prostate cancers. Cannabinoids have shown promise as analgesics for the treatment of both inflammatory and neuropathic pain. There is also evidence for a role of the endocannabinoid system in the control of emotional states, and cannabinoids could prove useful in decreasing and palliating post-traumatic stress disorder symptoms and anxiolytic disorders. The role of the endocannabinoid system in addictions has also been examined, and cannabinoids have been postulated as alternative and co-adjuvant treatments in some abuse syndromes, mainly in ethanol and opioid abuses. The expression of the endocannabinoid system in the eye suggests that it could be a potential therapeutic target for eye diseases. Considering the importance of the endocannabinoid system and the therapeutic potential of cannabinoids in this vast number of medical conditions, several clinical studies with cannabinoid-based medications are ongoing. In addition, some cannabinoid-based medications have already been approved in various countries, including nabilone and dronabinol capsules for the treatment of nausea and vomiting associated with chemotherapy, dronabinol capsules for anorexia, an oral solution of dronabinol for both vomiting associated with chemotherapy and anorexia, a Δ⁹-tetrahydrocannabinol/cannabidiol oromucosal spray for pain related to cancer and for spasticity and pain associated with multiple sclerosis, and an oral solution of cannabidiol for Dravet and Lennox–Gastaut syndromes. Here, we review the available efficacy, safety and tolerability data for cannabinoids in a range of medical conditions.
... Consequently, cannabinoids could be a good strategy as co-adjuvant treatments. In fact, a clinical study is currently being performed to evaluate the efficacy and safety of a cannabinoid-based spray containing the two major natural cannabinoids present in Cannabis sativa, THC and CBD, in combination with temozolomide for the treatment of glioma (NCT01812603) (Holland et al., 2006;Zogopoulos et al., 2015). ...
Article
In the last decades, the endocannabinoid system has attracted a great interest in medicine and cancer disease is probably one of its most promising therapeutic areas. On the one hand, endocannabinoid system expression has been found altered in numerous types of tumours compared to healthy tissue, and this aberrant expression has been related to cancer prognosis and disease outcome, suggesting a role of this system in tumour growth and progression that depends on cancer type. On the other hand, it has been reported that cannabinoids exert an anticancer activity by inhibiting the proliferation, migration and/or invasion of cancer cells; and also tumour angiogenesis. However, some cannabinoids, at lower concentrations, may increase tumour proliferation, inducing cancer growth. The endocannabinoid system may be considered as a new therapeutic target, although further studies to fully establish the effect of cannabinoids on tumour progression remain necessary.
... As expected, due to its higher expression in glial than in neuronal cells, gliomas may also express the CB 2 receptor and, therefore, any potential anti-tumor action of cannabinoid receptor ligands should take into account the two receptors (Ellert-Miklaszewska et al., 2013;Zogopoulos et al., 2015). On the one hand, (De Jesús et al., 2010) have reported that the expression of the two proteins in human gliomas samples is diverse, i.e. gliomas having more CB 2 receptors have (relatively) less CB 1 receptors and vice versa. ...
Article
Immunochemical detection of G-protein-coupled receptors (GPCRs) in cells and tissues was a technical challenge for years. After the discovery of formation of GPCR dimers/trimers/tetramers in transfected cells, a most recent challenge has been to confirm receptor-receptor interactions in natural sources. The occurrence of dimers or higher order oligomers is important from a therapeutic point of view, mainly because their physiology/pharmacology is different from those of individual receptors. On the one hand, pathophysiological factors need to count more on GPCR dimers than on individual receptors. On the other hand, the expression of dimers, trimers, etc. may change in pathological conditions and/or along the course of a disease. This review will focus on G-protein-coupled receptor dimers, on how to detect them by novel histological techniques and on how the detection may be used in diagnosis and therapy of ailments of the central nervous system, for instance in neurodegenerative diseases and gliomas.
... In recent years, the endocannabinoid system (ES) has emerged as a new therapeutic target in variety of disorders associated with inflammation and tissue injury, including those of the neuronal, liver, renal and cardiovascular system as well as in physiological processes, including nociception (pain-sensation), appetite, lipid metabolism, gastrointestinal motility, cardiovascular modulation, motor activity and memory [5][6][7]. Additionally, cannabinoids (CBs)--endocannabinoids are evaluated and reviewed as substances exerting anti-inflammatory, anti-proliferative, anti-invasive, anti-metastatic and proapoptotic effects in different cancer types, both in vitro and in vivo animal models [8]. ...
... In recent years, the endocannabinoid system (ES) has emerged as a new therapeutic target in variety of disorders associated with inflammation and tissue injury, including those of the neuronal, liver, renal and cardiovascular system as well as in physiological processes, including nociception (pain-sensation), appetite, lipid metabolism, gastrointestinal motility, cardiovascular modulation, motor activity and memory [5][6][7]. Additionally, cannabinoids (CBs)--endocannabinoids are evaluated and reviewed as substances exerting anti-inflammatory, anti-proliferative, anti-invasive, anti-metastatic and proapoptotic effects in different cancer types, both in vitro and in vivo animal models [8]. ...
Article
Introduction: In recent years, the endocannabinoid system has emerged as a new therapeutic target in variety of disorders associated with inflammation and tissue injury, including those of the neuronal, liver, renal and cardiovascular system. The aim of the present review is to elucidate the effect of endocannabinoid system on ischemia reperfusion injury (IRI) in different organs and systems. Areas covered: The MEDLINE/PubMed database was searched for publications with the medical subject heading Cannabinoids* (CBs), CB receptors*, organ*, ischemia/reperfusion injury*, endocannabinoid* and system*. The initial relevant studies retrieved from the literature were 91 from PubMed. This number was initially limited to 35, after excluding the reviews and studies reporting data for receptors other than cannabinoid. Expert opinion: CB2 receptors may play an important compensatory role in controlling tissue inflammation and injury in cells of the neuronal, cardiovascular, liver and renal systems, as well as in infiltrating monocytes/macrophages and leukocytes during various pathological conditions of the systems (atherosclerosis, restenosis, stroke, myocardial infarction, heart, liver and renal failure). These receptors limit inflammation and associated tissue injury. On the basis of preclinical results, pharmacological modulation of CB2 receptors may hold a unique therapeutic potential in stroke, myocardial infarction, atherosclerosis, IRI and liver disease.
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Background Cannabis for cancer is very topical and, given the use of illicit cannabis preparations used in this vulnerable population, research investigating standardised, quality-assured medicinal cannabis is critical to inform clinicians and assist patient safety. Methods A randomized trial involving adult patients diagnosed with a high-grade glioma, no history of substance abuse, liver or kidney damage or myocardial infarction were eligible for inclusion in a tolerability study on two different ratios of medicinal cannabis. Baseline screening of brain morphology, blood pathology, functional status, and cognition was conducted. A retrospective control group was used for comparison for secondary outcomes. Results Participants (n=88) were on average 53.3 years old. A paired t-test assessed the Functional Assessment of Cancer Therapy for Brain Cancer (FACT-Br) between groups from baseline to week 12 found that the 1:1 ratio favoured both physical (p=0.025) and functional (p=0.014) capacity and improved sleep (p=0.009). Analysis of changes from baseline to week 12 also found 11% of 61 participants had a reduction in disease, 34% were stable, 16% had slight enhancement, and 10% had progressive disease. No serious adverse events occurred. Side effects included dry mouth, tiredness at night, dizziness, drowsiness. Conclusion This study demonstrated that a single nightly dose of THC-containing medicinal cannabis was safe, had no serious adverse effects and was well tolerated in patients. Medicinal cannabis significantly improved sleep, functional wellbeing, and quality of life. Clinical Trial Registration Australian New Zealand Clinical Trials Registry (ANZCTR) http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373556&isReview=true , identifier ACTRN12617001287325.
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Geçmişte pek çok bitki, bitki parçası, meyvesi, tohumu ve bunlardan hazırlanan ürünler (iksirler ve karışımlar) tedavi amaçlı olarak kullanılmıştır. Bugün farmasötik sanayide gelinen aşamadan dolayı geçmişe bakıldığında, kullanılan birçok iksirlerin ve karışımların işe yaramadığı, hatta bazılarının zararlı bile olduğu bilinmektedir. Bununla birlikte, bazı bitkilerin bazı hastalıklara farklı mekanizmalarla olumlu etkileri olabildiği bilimsel olarak kanıtlanırken aynı zamanda bir kısmı ilaç etken maddesi olarak eczanelerde de yer alabilmektedir. Bu bitkilerden biri olan kenevir, insanlar tarafından yüzyıllar boyunca tekstil lifi, ilaç, keyif verici madde, tıbbı tedavi amaçlı olarak ve dini ritüellerde günlük adanma işlemleri sırasında kullanılmıştır.
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Cannabinoids represent unique compounds for treating tumors, including astrocytomas. Whether CB(1) and CB(2) receptors mediate this therapeutic effect is unclear. We generated astrocytoma subclones that express set levels of CB(1) and CB(2), and found that cannabinoids induce apoptosis only in cells expressing low levels of receptors that couple to ERK1/2. In contrast, cannabinoids do not induce apoptosis in cells expressing high levels of receptors because these now also couple to the prosurvival signal AKT. Remarkably, cannabinoids applied at high concentration induce apoptosis in all subclones independently of CB(1), CB(2) and AKT, but still through a mechanism involving ERK1/2. The high expression level of CB(1) and CB(2) receptors commonly found in malignant astrocytomas precludes the use of cannabinoids as therapeutics, unless AKT is concomitantly inhibited, or cannabinoids are applied at concentrations that bypass CB(1) and CB(2) receptors, yet still activate ERK1/2.
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Cannabinoids - the active components of Cannabis sativa and their derivatives - exert palliative effects in cancer patients by preventing nausea, vomiting and pain and by stimulating appetite. In addition, these compounds have been shown to inhibit the growth of tumour cells in culture and animal models by modulating key cell-signalling pathways. Cannabinoids are usually well tolerated, and do not produce the generalized toxic effects of conventional chemotherapies. So, could cannabinoids be used to develop new anticancer therapies?
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Various reports have shown that cannabinoids (the active components of marijuana and their derivatives) can reduce tumour growth and progression in animal models of cancer, in addition to their well-known palliative effects on some cancer-associated symptoms. This Opinion article discusses our current understanding of cannabinoids as antitumour agents, focusing on recent insights into the molecular mechanisms of action, including emerging resistance mechanisms and opportunities for combination therapy approaches. Such knowledge is required for the optimization of preclinical cannabinoid-based therapies and for the preliminary clinical testing that is currently underway.
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Gliomas are the most important group of malignant primary brain tumors and one of the most aggressive forms of cancer. During the last years, several studies have demonstrated that cannabinoids induce apoptosis of glioma cells and inhibit angiogenesis of gliomas in vivo. As the effects of cannabinoids rely on CB(1) and CB(2) receptors activation, the aim of the present study was to investigate both receptors protein expression in cellular membrane homogenates of human glial tumors using specific antibodies raised against these proteins. Additionally, we studied the functionality of the cannabinoid receptors in glioblastomas by using WIN 55,212-2 stimulated [(35)S]GTPgammaS binding. Western blot analysis showed that CB(1) receptor immunoreactivity was significantly lower in glioblastoma multiforme (-43%, n=10; p<0.05) than in normal post-mortem brain tissue (n=16). No significant differences were found for astrocytoma (n=6) and meningioma (n=8) samples. Conversely, CB(2) receptor immunoreactivity was significantly greater in membranes of glioblastoma multiforme (765%, n=9; p<0.05) and astrocytoma (471%, n=4; p<0.05) than in control brain tissue (n=10). Finally, the maximal stimulation of [(35)S]GTPgammaS binding by WIN 55,212-2 was significantly lower in glioblastomas (134+/-4%) than in control membranes (183+/-2%; p<0.05). The basal [(35)S]GTPgammaS binding and the EC(50) values were not significantly different between both groups. The present results demonstrate opposite changes in CB(1) and CB(2) receptor protein expression in human gliomas. These changes may be of interest for further research about the therapeutic effects of cannabinoids in glial tumors.
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According to the World Health Organization, the cases of death caused by cancer will have been doubled until the year 2030. By 2010, cancer is expected to be the number one cause of death. Therefore, it is necessary to explore novel approaches for the treatment of cancer. Over past years, the antitumorigenic effects of cannabinoids have emerged as an exciting field in cancer research. Apart from their proapoptotic and antiproliferative action, recent research has shown that cannabinoids may likewise affect tumor cell angiogenesis, migration, invasion, adhesion, and metastasization. This review will summarize the data concerning the influence of cannabinoids on these locomotive processes beyond modulation of cancer cell apoptosis and proliferation. The findings discussed here provide a new perspective on the antitumorigenic potential of cannabinoids.
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The newly discovered endocannabinoid system (ECS; comprising the endogenous lipid mediators endocannabinoids present in virtually all tissues, their G-protein-coupled cannabinoid receptors, biosynthetic pathways and metabolizing enzymes) has been implicated in multiple regulatory functions both in health and disease. Recent studies have intriguingly suggested the existence of a functional ECS in the skin and implicated it in various biological processes (e.g. proliferation, growth, differentiation, apoptosis and cytokine, mediator or hormone production of various cell types of the skin and appendages, such as the hair follicle and sebaceous gland). It seems that the main physiological function of the cutaneous ECS is to constitutively control the proper and well-balanced proliferation, differentiation and survival, as well as immune competence and/or tolerance, of skin cells. The disruption of this delicate balance might facilitate the development of multiple pathological conditions and diseases of the skin (e.g. acne, seborrhea, allergic dermatitis, itch and pain, psoriasis, hair growth disorders, systemic sclerosis and cancer).
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The most abundant malignant brain tumor in human is glioblastoma and patients with this type of tumor have a poor prognosis with high mortality. Glioblastoma are characterized particularly by fast growth and a dependence on blood vessel formation for survival. Cannabinoids (CBs) inhibit tumor growth by inducing apoptosis of tumor cells and impairing tumor angiogenesis. The distribution of CB1 and CB2 receptors in glioblastoma and associated endothelial vessels is still unknown. Tissue samples were collected consecutively after neurosurgery of 19 patients suspected glioblastoma and examined immunohistochemically for CB1 and CB2 receptor expression. Vessel endothelial cells of the sections were immunocytochemically identified by using a primary antibody against PECAM-1. Double labelling was performed for CB receptors and endothelial cells of the vessels by DAPI staining. In endothelia of control tissue, about 24% and 45% of the cells were positive for CB1 and CB2 receptors. In glioblastoma endothelial cells, CB1 and CB2 receptors were present in about 38% and 54% of the cells respectively. In comparison to CB1, an elevated CB2 receptor expression was identified in glioblastoma. The abundant expression and distribution of CB2 receptors in glioblastoma and particularly endothelial cells of glioblastoma indicate that impaired tumor growth in presence of CB may be associated with CB2 activation. Selective CB2 agonists might become important targets attenuating vascular endothelial growth factor (VEGF) signalling and thereby diminishing neoangiogenesis and glioblastoma growth.
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Cannabinoids, the active components of the hemp plant Cannabis sativa, along with their endogenous counterparts and synthetic derivatives, have elicited anti-cancer effects in many different in vitro and in vivo models of cancer. While the various cannabinoids have been examined in a variety of cancer models, recent studies have focused on the role of cannabinoid receptor agonists (both CB(1) and CB(2)) in the treatment of estrogen receptor-negative breast cancer. This review will summarize the anti-cancer properties of the cannabinoids, discuss their potential mechanisms of action, as well as explore controversies surrounding the results.
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Glycine has been shown to possess important functions as a bidirectional neurotransmitter. At synaptic clefts, the concentration of glycine is tightly regulated by the uptake of glycine released from nerve terminals into glial cells by the transporter GLYT1. It has been recently demonstrated that protein kinase C (PKC) mediates the downregulation of GLYT1 activity in several cell systems. However, it remains to be elucidated which subtypes of PKC might be important in the regulation of GLYT1 activity. In this study, we attempted to make clear the mechanism of the phorbol 12-myristate 13-acetate (PMA)-suppressed uptake of glycine in C6 glioma cells which have the native expression of GLYT1. In C6 cells, the expression of PKCalpha, PKCdelta, and PKCvarepsilon of the PMA-activated subtypes was detected. The PMA-suppressed action was fully reversed by the removal of both extracellular and intracellular Ca(2+). Furthermore, the inhibitory effects of PMA or thymeleatoxin (THX), which is a selective activator of conventional PKC (cPKC), were blocked by the downregulation of all PKCs expressed in C6 cells by long-term incubation with THX, or pretreatment with GF109203X or Gö6983, which are broad inhibitors of PKC, or Gö6976, a selective inhibitor of cPKC. On the other hand, treatment of C6 cells with ingenol, a selective activator of novel PKCs, especially PKCdelta and PKCvarepsilon, did not affect the transport of glycine. Silencing of PKCdelta expression by using RNA interference or pretreatment with the inhibitor peptide for PKCvarepsilon had no effect on the PMA-suppressed uptake of glycine. Together, these results suggest PKCalpha to be a crucial factor in the regulation of glycine transport in C6 cells.
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We found a dose-related decrease in DNA synthesis in transformed cell cultures treated with delta9-tetrahydrocannabinol (delta9-THC). The decrease, observed over a 4-hour period, was not accompanied by a change in the radioactive precursor pool as compared to that of control culture. The distribution of labeled products clearly differed from that observed after treatment with cytosine arabinoside. delta9-THC inhibited DNA synthesis at some point beyond the uptake of 3H-thymidine.
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Lewis lung adenocarcinoma growth was retarded by the oral administration of delta9-tetrahydrocannabinol (delta9-THC), delta8-tetrahydrocannabinol (delta8-THC), and cannabinol (CBN), but not cannabidiol (CBD). Animals treated for 10 consecutive days with delta9-THC, beginning the day after tumor implantation, demonstrated a dose-dependent action of retarded tumor growth. Mice treated for 20 consecutive days with delta8-THC and CBN had reduced primary tumor size. CBD showed no inhibitory effect on tumor growth at 14, 21, or 28 days. Delta9-THC, delta8-THC, and CBN increased the mean survival time (36% at 100 mg/kg, 25% at 200 mg/kg, and 27% at 50 mg/kg, respectively), whereas CBD did not. Delta9-THC administered orally daily until death in doses of 50, 100, or 200 mg/kg did not increase the life-spans of (C57BL/6 times DBA/2)F1 (BDF1) mice hosting the L1210 murine leukemia. However, delta9-THC administered daily for 10 days significantly inhibited Friend leukemia virus-induced splenomegaly by 71% at 200 mg/kg as compared to 90.2% for actinomycin D. Experiments with bone marrow and isolated Lewis lung cells incubated in vitro with delta9-THC and delta8-THC showed a dose-dependent (10(-4)-10(-7)) inhibition (80-20%, respectively) of tritiated thymidine and 14C-uridine uptake into these cells. CBD was active only in high concentrations (10(-4)).
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The Radiation Therapy Oncology Group (RTOG) and the Eastern Cooperative Oncology Group (ECOG) conducted a phase III trial in patients with malignant gliomas to evaluate 4 treatment arms: 1) 60 Gy to the whole brain; 2) 60 Gy plus 10-Gy boost; 3) 60 Gy plus carmustine (BCNU); and 4) 60 Gy plus semustine plus dacarbazine. Between September 1974 and March 1979, 626 patients with malignant gliomas were treated on protocol RTOG 7401/ECOG 1374. Each institution chose a subset of the treatments to which the patients would be randomized. Patients were stratified according to subset and randomized to the 4 treatment arms. There were no differences in survival among treatment arms. For patients greater than 60 years of age, the addition of chemotherapy to radiation therapy did not improve survival. For patients aged 40-60 years, there was a statistically significant increase in overall survival when BCNU was added to 60 Gy (P less than .01), with an increase in 2-year survival from 8% to 23%. This beneficial effect of BCNU is apparent in both histological groups (astrocytoma with atypical or anaplastic foci and glioblastoma multiforme). Although few confirmatory autopsies are available, long-term survival in patients with astrocytomas with atypical and anaplastic foci who were treated with 60 Gy plus BCNU (5-yr survival, 22%) suggests no significant late CNS toxicity, compared to 60 Gy alone (5-yr survival, 15%). This is confirmed by comparable neurological function in long-term survivors.
Article
To examine which growth factors correlate with neovascularization in human brain tumors, the mRNA levels of transforming growth factor alpha, transforming growth factor beta, basic fibroblast growth factor, and vascular endothelial growth factor (VEGF) genes were determined by a Northern blot analysis in surgically obtained human gliomas and meningiomas. The vascular development was determined by counting the number of microvessels which were immunostained with von Willebrand factor. We normalized the growth factor mRNA levels versus the glyceraldehyde phosphate dehydrogenase mRNA level. In the 17 gliomas and 16 meningiomas examined, the mRNA of transforming growth factors alpha and beta, basic fibroblast growth factor, and VEGF were expressed at various levels. Among those 4 growth factors, the mRNA levels of VEGF, but not those of transforming growth factors alpha and beta and basic fibroblast growth factor, correlated significantly with vascularity in both gliomas (correlation coefficient r = 0.499; P < 0.05) and meningiomas (correlation coefficient r = 0.779; P < 0.001). These findings thus suggest that VEGF may be a positive factor in tumor angiogenesis in both human gliomas and meningiomas.
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To conduct a Phase II one-arm study to evaluate the long-term efficacy and safety of accelerated fractionated radiotherapy combined with intravenous carboplatin for patients with previously untreated glioblastoma multiforme tumors. Between 1988 and 1992, 83 patients received 1.9-2.0 Gy radiation three times a day with 2-h infusions of 33 mg/m2 carboplatin for two 5-day cycles separated by 2 weeks; following radiotherapy, patients received procarbazine, lomustine (CCNU), and vincristine (PCV) for 1 year or until tumor progressed. Eighty-three patients were evaluable for analysis. Seventy-four of the 83 patients (89%) received one or more courses of PCV; their median survival was 55 weeks. Total resection was performed in 20% (15 of 74), subtotal resection in 69% (51 of 74), and biopsy in 11% (8 of 74); reoperation (total or subtotal resection) was performed in 28 patients (37%). Survival was worst for those > or = 61 year old (median 35 weeks). Fits of the Cox proportional hazards regression model showed covariates individually predictive of improved survival were younger age (p < 0.01), smaller log of radiation volume (p = 0.008), total or subtotal resection vs. biopsy (p = 0.056), and higher Karnofsky performance status (p = 0.055). A multivariate analysis showed that age (p = 0.013) and extent of initial surgery (p = 0.003) together were predictive of a better survival with no other variables providing additional significance. Only 8.4% (7 of 83) of patients had clinically documented therapy-associated neurotoxicity ("radiation necrosis"). When comparable selection criteria were applied, the survival in this study is similar to the results currently attainable with other chemoradiation approaches. The relative safety of accelerated fractionated radiotherapy, as used in this study with carboplatin, enables concomitant full-dose administration of chemotherapy or radiosensitizing agents in glioblastoma multiforme patients.
Article
In patients with cerebral astrocytomas treated with nitrosourea-based chemotherapy, to determine whether age is predictive of response, time to progression, survival, or rate of complications. Retrospective analysis of neuroimaging studies and clinical data. University hospital with a busy neuro-oncology service. One hundred forty-eight patients with pathologically confirmed malignant astrocytomas or recurrent astrocytomas. Partial response occurred in 39% of patients aged < 40 years, in 17% of those aged 40 to 59, and in only 5% of those aged > or = 60 (p < 0.001). Median time to progression after chemotherapy was 23 weeks in patients aged < 60 and 6 weeks in patients aged > or = 60 (p < 0.001). Median survival after chemotherapy was 43 weeks in patients aged < 60 but only 24 weeks in patients aged > or = 60 (p < 0.001). Differences between age groups in response rate, time to progression, and survival persisted with adjustment for tumor grade. The risk of myelosuppressive complications requiring hospitalization was significantly related to age (p = 0.03); such complications occurred in 35% of patients aged > or = 60 and 16% of patients under 60 years. Age is strongly predictive of the likelihood of a response to chemotherapy, time to progression, survival, and risk of myelosuppressive complications. Patients aged > or = 60 have a lower change of benefit and an increased risk of myelosuppressive complications from chemotherapy for astrocytomas compared with younger patients.
Article
We tested adjuvant chemotherapy combining dibromodulcitol (DBD) and bischloroethylnitrosourea (BCNU) given postoperatively to adults with newly diagnosed supratentorial malignant gliomas. We enrolled 269 patients, 255 of whom were eligible. After surgery, we treated all patients with radiation therapy, using a median dose of 60 Gy given in 30 fractions. After randomization, patients in the chemotherapy group also received (1) six weekly courses, administered during irradiation, of DBD 700 mg/m2 and (2) one to nine (median, four) courses, administered during the first year following radiation therapy, of DBD 1,000 mg/m2 on day 1 and BCNU 150 mg/m2 on day 2, with the course being repeated every 6 weeks. Patients treated with radiation therapy along with DBD plus BCNU (group 2) had significantly longer survival time (p = 0.044) and time to progression (p = 0.003) than did those treated with radiation therapy alone (group 1). The median survival time was 13.0 months for group 2 and 10.4 months for group 1; the median time to progression was 8.1 months for group 2 and 6.7 months for group 1. The percentage of patients alive at 18 and 24 months was 34% and 21% in group 2 compared with 21% and 12% in group 1. DBD plus BCNU is an effective adjuvant therapy for malignant glioma.
Article
This study was designed to evaluate strategies to overcome the resistance of anaplastic gliomas of the brain to external beam radiotherapy (ERT) plus carmustine (BCNU). Patients were > or = 15 years of age, had a histologic diagnosis of malignant glioma, and a Karnofsky performance status (KPS) > or = 60%. In Randomization 1, patients were assigned to receive either ERT alone (61.2 Gy) or ERT plus mitomycin C (Mito, IV 12.5 mg/m(2)) during the first and fourth week of ERT. After this treatment, patients went on to Randomization 2, where they were assigned to receive either BCNU (i.v. 200 mg/m(2)) given at 6-week intervals or 6-mercaptopurine (6- MP, 750 mg/m(2) IV daily for 3 days every six weeks), with BCNU given on the third day of the 6-MP treatment. Three hundred twenty-seven patients underwent Randomization 1. One hundred sixty-four received ERT alone, and 163 received ERT + Mito [average 52.7 years; 63% male; 69% glioblastoma multiforme (GBM); 66% had a resection; 56% KPS > or = 90%]. Step-wise analysis of survival from Randomization 1 or 2 indicates that survival was significantly diminished by: (a) age > or = 45 years (b) KPS < 90%; (c) GBM/gliosarcoma histology; (d) stereotactic biopsy as opposed to open biopsy or resection. Median survival from Randomization 1 in both arms (ERT + Mito) was 10.8 months. Median survival from Randomization 2 was 9.3 months for BCNU/6MP vs. 11.4 months for the BCNU group (p = 0.35). Carmustine/6-MP showed a possible survival benefit for histologies other than GBM/GS. Two hundred and thirty-three patients underwent Randomization 2. The proportion of patients in the ERT group who terminated study prior to Randomization 2 was significantly less in the ERT group than in the ERT + Mito group (20 vs. 37%, p < 0.001). (a) The addition of Mito to ERT had no impact on survival; (b) patients treated with ERT + Mito were at greater risk of terminating therapy prior to Randomization 2; (c) there was not a significant survival benefit to the addition of 6-MP to BCNU.
Article
Two cannabinoid receptors have been identified to date; one is located predominantly in the central nervous system (CB1), whereas the other is located exclusively in the periphery (CB2). The purposes of this study were to explore further the binding requirements of the CB2 receptor and to search for compounds displaying distinct affinities for either cannabinoid receptor. The binding affinities of a series of cannabinoids tested previously at the CB1 receptor were determined at cloned human CB1 and CB2 receptors using a filtration assay. In addition, possible allosteric regulation of the CB2 receptor was examined. Sodium and a GTP analog elicited a concentration-dependent decrease in specific binding to the CB2 receptor. The affinity of cannabinol for CB2 receptors (Ki = 96.3 +/- 14 nM) was confirmed to be in approximately the same range as that of delta 9-THC (Ki = 36.4 +/- 10 nM). Affinities at cloned CB1 and CB2 receptors were compared with affinities determined in the brain. Although most of the chosen compounds did not discriminate between CB1 and CB2, several ligands were identified that showed selectivity. Affinity ratios demonstrated that two 2'-fluoro analogs of anandamide were over 23-fold selective for the CB1 receptor and confirmed the CB1 selectivity of SR141716A {N- (piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboxamidehydrochloride}. In addition, WIN-55, 212-2 {(R)-(+)-[2, 3-dihydro-5-methyl-3-[(4-morpholinyl) methyl] pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthalenyl) methanone} and a closely related propyl indole analog were shown to be 6.75- and 27.5- fold selective, respectively, for the CB2 receptor. These ligands can now serve as a basis for the design of compounds with even greater selectivity.
Article
Cannabis is one of the most widely used drugs throughout the world. The psychoactive constituent of cannabis, delta 9-tetrahydrocannabinol (delta 9-THC), produces a myriad of pharmacological effects in animals and humans. For many decades, the mechanism of action of cannabinoids, compounds which are structurally similar to delta 9-THC, was unknown. Tremendous progress has been made recently in characterizing cannabinoid receptors both centrally and peripherally and in studying the role of second messenger systems at the cellular level. Furthermore, an endogenous ligand, anandamide, for the cannabinoid receptor has been identified. Anandamide is a fatty-acid derived compound that possesses pharmacological properties similar to delta 9-THC. The production of complex behavioral events by cannabinoids is probably mediated by specific cannabinoid receptors and interactions with other neurochemical systems. Cannabis also has great therapeutic potential and has been used for centuries for medicinal purposes. However, cannabinoid-derived drugs on the market today lack specificity and produce many unpleasant side effects, thus limiting therapeutic usefulness. The advent of highly potent analogs and a specific antagonist may make possible the development of compounds that lack undesirable side effects. The advancements in the field of cannabinoid pharmacology should facilitate our understanding of the physiological role of endogenous cannabinoids.
Article
We devised a treatment protocol for anaplastic gliomas consisting of:(a) chemotherapy prior to radiotherapy (b) a second chemotherapy regimen at tumor recurrence (c) repeated surgery whenever possible. 41 Anaplastic Astrocytoma (AA), 16 Anaplastic oligoastrocytoma (AOA) and 14 anaplastic oligodendroglioma (AOD) patients were treated. After surgery all patients received 5-6 cycles of carmustine+Cisplatinum chemotherapy. Radiotherapy was started during the last 2-3 cycles of chemotherapy. 17 patients (30.5%) were reoperated on at recurrence. All recurring patients underwent PVC chemotherapy. At this moment disease recurred in 56 patients. Median TTP was 24.5, 38.7 and 58.2 months for AA, AOA and AOD respectively. Median ST was 38.8, 71.8 and 73 months. In conclusion our sandwich protocol of prior chemotherapy, overlapping irradiation with second chemotherapy and, in favourable cases, a second surgical intervention, is of benefit in patients with anaplastic gliomas.
Article
A Phase II study with a combination of BCNU and alpha-interferon (IFN) was conducted in patients with high-grade glioma recurrent after surgery and radiation treatment in order to investigate tumor control and toxicity. Twenty-one non-chemotherapy pretreated patients were administered 6 MU alpha-IFN in a 2-h infusion followed by 150 mg/m2 BCNU i.v. on day 1. Three MU alpha-IFN were subsequently administered subcutaneously on alternating days three times a week, until recycling of the whole procedure on day 42. Among 21 patients, partial remission was obtained in 7 (33%; 95% CI = 15-57) and stable disease in 6 (29%; CI = 11-52); overall Kaplan-Meier median time to progression (TTP) was 4.5 months (CI = 4-9) and the overall median survival time (MST) was 7 months (CI = 5-13). In patients who underwent surgical redebulking prior to chemotherapy, TTP and MST were 9 (CI = 7-14) and 15 months (CI = 11.0-39.0); in patients who were not operated on again before chemotherapy, these values were 4 (CI = 2-5; log rank test, p = 0.0026) and 5.5 months (CI = 4-7; log rank test, p = 0.0012) respectively. The results of this regimen in relapsing patients, especially following surgical redebulking, are encouraging; toxicity is acceptable, and further studies on combined alpha-IFN and multiple-agent chemotherapy are warranted.
Article
There are at least two types of cannabinoid receptors, CB1 and CB2, both coupled to G-proteins. CB1 receptors are present in the central nervous system and CB1 and CB2 receptors in certain peripheral tissues. The existence of endogenous cannabinoid receptor agonists has also been demonstrated. These discoveries have led to the development of selective cannabinoid CB1 and CB2 receptor ligands. This review focuses on the classification, binding properties, effector systems and distribution of cannabinoid receptors. It also describes the various cannabinoid receptor agonists and antagonists now available and considers the main in vivo and in vitro bioassay methods that are generally used.
Article
This study was designed to evaluate a combined modality treatment for malignant gliomas using radiation therapy with a radiosensitizer and an adjuvant chemotherapy regimen designed to modify resistance to BNCU. Patients were eligible if they were 15 years of age or older, and had newly diagnosed glioblastoma multiforme (GBM), or anaplastic glioma (AG). Treatment consisted of external beam radiotherapy given to a dose of 60 Gy using a single daily fraction Monday to Friday. Concurrent hydroxyurea at a dose of 300 mg/m2 every 6 h every other day was given during radiation. Following radiotherapy, patients were then treated with BCNU and 6-Thioguanine (6TG). The 6-TG was given by mouth every 6 h for 12 doses prior to BCNU. Patients were initially treated with 60 mg/m2/dose of 6TG, with escalation to a maximum dose of 100 mg/m2/dose. The primary study end points were time to tumor progression and survival. A total of 245 eligible patients were enrolled from 1/18/88 to 12/26/91. The histologic subtypes included 135 GBM, and 110 with AG (103 with anaplastic astrocytoma, 7 with high-grade mixed oligoastrocytoma). For the GBM group, the median time to tumor progression (TTP) and median survival were 33 (95% CI 26, 39) and 56 (95% CI 49, 69) weeks, respectively. For the AG group the median TTP was 282 weeks (95% lower confidence bound = 155 weeks). Median survival for this group has not been reached (95% lower confidence bound = 284 weeks) with a median follow-up for surviving patients of 298 weeks. A proportional hazards model was used to look at potential prognostic factors for survival, including initial Karnofsky Performance Scale (KPS), age, and extent of surgery, as well as dose of 6TG. Higher KPS, and lower age, predicted for longer survival (p < 0.01, < 0.001) in GBM patients; lower age was significant (p = 0.05) for AG cases. A higher (greater than 95 mg/m2) or lower dose of 6TG was not statistically significant in this model. This therapy was no more effective in patients with GBM than other reported series. In patients with malignant gliomas other than GBM, prolonged progression-free and overall survival is noted, without a median survival reached at the time of this report. In this subset of AG patients, survival is comparable to recent studies using halogenated prymidines during radiation and Procarbazine, CCNU, and Vincristine (PCV) as adjuvant chemotherapy.
Article
Despite more than two decades of clinical research with chemotherapy, the outcome of malignant gliomas remains poor. Recent years have seen major advances in elucidation of the biology of these tumors, which in turn have led to the current development of innovative therapeutic strategies. The question confronting us at the end of the 1990s is whether we should continue to use and investigate chemotherapy or whether the time has come for experimental treatments. As a contribution to this debate, we reviewed the abundant literature on chemotherapy of malignant glioma, paying special attention to methodological features. The new treatment approaches based on current knowledge about glioma biology are then briefly summarized. Assessment of more than 20 years of chemotherapy trials is discouraging despite a few areas of modest success. Only patients with specific histology (oligodendroglioma, anaplastic astrocytoma) and good prognostic factors (young age, good performance status) may benefit from chemotherapy, with a possible reversal of neurological dysfunction. However, the real impact on survival is small (anaplastic astrocytoma) or undefined (oligodendroglioma). Furthermore, it is unfortunately obvious that the outcome of glioblastoma patients is not significantly modified by chemotherapy. We believe the time has come to explore the potential of novel biological therapies in glioblastoma patients. This could also be proposed for anaplastic astrocytoma and oligodendroglioma patients after failure of chemotherapy.
Article
delta9-Tetrahydrocannabinol (THC), the major active component of marijuana, induced apoptosis in C6.9 glioma cells, as determined by DNA fragmentation and loss of plasma membrane asymmetry. THC stimulated sphingomyelin hydrolysis in C6.9 glioma cells. THC and N-acetylsphingosine, a cell-permeable ceramide analog, induced apoptosis in several transformed neural cells but not in primary astrocytes or neurons. Although glioma C6.9 cells expressed the CBI cannabinoid receptor, neither THC-induced apoptosis nor THC-induced sphingomyelin breakdown were prevented by SR141716, a specific antagonist of that receptor. Results thus show that THC-induced apoptosis in glioma C6.9 cells may rely on a CBI receptor-independent stimulation of sphingomyelin breakdown.
Article
Cannabis is the most widely used illicit drug in many developed societies. Its health and psychological effects are not well understood and remain the subject of much debate, with opinions on its risks polarised along the lines of proponents' views on what its legal status should be. An unfortunate consequence of this polarisation of opinion has been the absence of any consensus on what health information the medical profession should give to patients who are users or potential users of cannabis. There is conflicting evidence about many of the effects of cannabis use, so we summarise the evidence on the most probable adverse health and psychological consequences of acute and chronic use. This uncertainty, however, should not prevent medical practitioners from advising patients about the most likely ill-effects of their cannabis use. Here we make some suggestions about the advice doctors can give to patients who use, or are contemplating the use, of this drug.
Article
Angiogenesis is a possible target in the treatment of human gliomas. To evaluate the role of 3 growth factors, vascular endothelial growth factor (VEGF), hepatocyte growth factor/scatter factor (HGF/SF) and basic fibroblast growth factor (bFGF), in the angiogenic cascade, we determined their levels in extracts of 71 gliomas by enzyme-linked immunosorbent assay (ELISA). The levels of bFGF were only marginally different between gliomas of World Health Organization (WHO) grade II (low grade) and grades III and IV (high grade). In contrast, the mean concentrations of VEGF were 11-fold higher in high-grade tumors and those of HGF/SF 7-fold, respectively. Both were highly significantly correlated with microvessel density (p < 0.001) as determined by immunostaining for factor VIII-related antigen. In addition, VEGF and HGF/SF appeared to be independent predictive parameters for glioma microvessel density as determined by multiple regression analysis. We measured the capacity of all 3 factors to induce endothelial tube formation in a collagen gel. In this assay, bFGF was found to be an essential cofactor with which VEGF as well as HGF/SF were able to synergize independently. According to the concentrations of angiogenic factors, extracts from high-grade tumors were significantly more potent in the tube formation assay than the low-grade extracts (p = 0.02). Adding neutralizing antibodies to bFGF, VEGF and HGF/SF together with the extracts, tube formation was inhibited by up to 98%, 62% and 54%, respectively. Our findings suggest that bFGF is an essential cofactor for angiogenesis in gliomas, but in itself is insufficient as it is present already in the sparsely vascularized low-grade tumors. Upon induction of angiogenesis in high-grade tumors, bFGF may synergize with rising levels of not only VEGF but possibly also with HGF/SF, which appears here to be an independent angiogenic factor.
Article
The effect of delta9-tetrahydrocannabinol (THC), the major psycho-active component of marijuana, in human prostate cancer cells PC-3 was investigated. THC caused apoptosis in a dose-dependent manner. Morphological and biochemical changes induced by THC in prostate PC-3 cells shared the characteristics of an apoptotic phenomenon. First, loss of plasma membrane asymmetry determined by fluorescent anexin V binding. Second, presence of apoptotic bodies and nuclear fragmentation observed by DNA staining with 4',6-diamino-2-phenylindole (DAPI). Third, presence of typical 'ladder-patterned' DNA fragmentation. Central cannabinoid receptor expression was observed in PC-3 cells by immunofluorescence studies. However, several results indicated that the apoptotic effect was cannabinoid receptor-independent, such as lack of an effect of the potent cannabinoid agonist WIN 55,212-2, inability of cannabinoid antagonist AM 251 to prevent cellular death caused by THC and absence of an effect of pertussis toxin pre-treatment.
Article
The synthesis and pharmacology of 15 1-deoxy-delta8-THC analogues, several of which have high affinity for the CB2 receptor, are described. The deoxy cannabinoids include 1-deoxy-11-hydroxy-delta8-THC (5), 1-deoxy-delta8-THC (6), 1-deoxy-3-butyl-delta8-THC (7), 1-deoxy-3-hexyl-delta8-THC (8) and a series of 3-(1',1'-dimethylalkyl)-1-deoxy-delta8-THC analogues (2, n = 0-4, 6, 7, where n = the number of carbon atoms in the side chain-2). Three derivatives (17-19) of deoxynabilone (16) were also prepared. The affinities of each compound for the CB1 and CB2 receptors were determined employing previously described procedures. Five of the 3-(1',1'-dimethylalkyl)-1-deoxy-delta8-THC analogues (2, n = 1-5) have high affinity (Ki = < 20 nM) for the CB2 receptor. Four of them (2, n = 1-4) also have little affinity for the CB1 receptor (Ki = > 295 nM). 3-(1',1'-Dimethylbutyl)-1-deoxy-delta8-THC (2, n = 2) has very high affinity for the CB2 receptor (Ki = 3.4 +/- 1.0 nM) and little affinity for the CB1 receptor (Ki = 677 +/- 132 nM).
Article
Spontaneous involution of pilocytic astrocytoma has been reported in children, particularly in those with neurofibromatosis Type 1. However, this rare occurrence has not been documented in adults. In this report the authors describe two cases of adults with pilocytic astrocytoma. One patient had a tumor in the thalamus and the other in the hypothalamus and optic chiasm; both patients underwent partial resection of the tumor. The initial magnetic resonance (MR) images demonstrated reduction in size of the tumors, and subsequent MR images obtained several months later revealed marked further involution with reduction in size and enhancement. The possible mechanisms for this uncommon occurrence are discussed.
Article
Cannabinoids exert most of their effects through the CB(1) receptor. This G-protein-coupled receptor has been shown to be functionally coupled to inhibition of adenylyl cyclase, modulation of ion channels, and activation of extracellular signal-regulated kinase. Using Chinese hamster ovary cells stably transfected with the CB(1) receptor cDNA, we show here that Delta(9)-tetrahydrocannabinol (THC), the major active component of marijuana, induces the activation of c-Jun N-terminal kinase (JNK). Western blot analysis showed that both JNK-1 and JNK-2 were stimulated by THC. The effect of THC was also exerted by endogenous cannabinoids (anandamide and 2-arachidonoylglycerol) and synthetic cannabinoids (CP-55,940, HU-210, and methanandamide), and was prevented by the selective CB(1) antagonist SR141716. Pertussis toxin, wortmannin, and a Ras farnesyltransferase inhibitor peptide blocked, whereas mastoparan mimicked, the CB(1) receptor-evoked activation of JNK, supporting the involvement of a G(i)/G(o)-protein, phosphoinositide 3'-kinase and Ras. THC-induced JNK stimulation was prevented by tyrphostin AG1296, pointing to the implication of platelet-derived growth factor receptor transactivation, and was independent of ceramide generation. Experiments performed with several types of neural cells that endogenously express the CB(1) receptor suggested that long-term JNK activation may be involved in THC-induced cell death. The CB(1) cannabinoid receptor was also shown to be coupled to the activation of p38 mitogen-activated protein kinase. Data indicate that activation of JNK and p38 mitogen-activated protein kinase may be responsible for some of the cellular responses elicited by the CB(1) cannabinoid receptor.