Chemotherapy Of Aa And Gbmhistorical Overview

In the 1960s and 1970s, surgical resection and postoperative external beam radiation therapy were established as the standard treatment approach for patients with AA and GBM 5,14 . However, in the late 1970s, investigators began to evaluate chemotherapy as a potential treatment modality when it became obvious that surgical resection and radiation therapy were not curative in the vast majority of patients, and that other forms of treatment were desperately needed to improve survival 20-24 . Over...

Phase Ii Trials

Temozolomide is an imidazole tetrazinone that undergoes chemical conversion to the active methylating agent under physiologic conditions. In a phase II trial of temozolomide in patients with progressive low-grade glioma, temozolomide was administered orally once a day for five consecutive days (in a fasting state) at a starting dose of 200 mg m2 day 33 . Treatment cycles were repeated every 28 days following the first daily dose of temozolomide. The study objectives were two-fold to determine...

Neuroimaging And Initial Treatment

The most sensitive technique to diagnose medulloblastoma is neuro-imaging with contrast-enhanced MRI 1,3-5,13,17 . MRI is more sensitive than CT for tumors within the posterior fossa and has the added benefit of midsagittal images. Hydrocephalus (75 to 85 per cent of cases) is clearly demonstrated with either modality. On T2 images, the tumor is a heterogeneous high signal lesion within the cerebellum (midline or hemispheric). Regions of calcification, cyst, necrosis, or hemorrhage are not...

CDK46D cyclins

A requirement for the D-type cyclins to drive cells through G1 was identified in experimental cell culture studies where cyclin D1 overexpression was shown to be sufficient to enable G1 progression 13 . The D-type cyclins bind to CDKs 4 and 6 to form active kinase complexes that regulate progression through RP 14 . Whereas mice lacking CDK4 expression have a normal phenotype and growth profile, mice engineered to overexpress CDK4 are predisposed to tumorigenesis at an accelerated rate 15,16 ....

Figure

Azo-PCB into two separate azoxy-PCB derivatives, which have significantly greater antitumor activity than PCB or azo-PCB 90,91 . Once activated, PCB alkylates DNA at the O6 position of guanine 92 . In addition, PCB can induce DNA strand breakage and inhibit DNA, RNA, and protein synthesis. PCB has further pharmacological properties, including activity as a monoamine oxidase-inhibitor and a disulfiram-like effect 8,21 . Potential interactions (i.e., acute hypertension) can occur if PCB is taken...

Clinical Bbbd Technique

Intra-arterial infusion of a large volume of hypertonic mannitol (25 per cent, warmed). Focal motor seizures occur during approximately 7 per cent of BBBD procedures (most often in conjunction with methotrexate), thus general anesthesia provides the capability of rapid control of seizures if necessary. A femoral artery is catheterized and a selected intra-cranial artery (either an internal carotid or a vertebral artery) is accessed. The transfemoral catheter is placed at cervical vertebrae 1-2...

Intra Arterial Chemotherapy

ABSTRACT Intra-arterial (IA) chemotherapy is a form of regional delivery to brain tumors, designed to enhance the intra-tumoral concentrations of a given drug, in comparison to the intravenous route. Drugs that are likely to be benefit from IA delivery have a rapid systemic clearance and include carmustine and other nitrosoureas, cisplatin, carboplatin, etopo-side, and methotrexate. Clinical studies have demonstrated activity of IA chemotherapy approaches for low- and high-grade gliomas,...

Molecular Subsets of Brain Tumors

DNA microarray analyses have shown that different subtypes of gliomas have distinct gene-expression profiles, which can be distinguished from one another and from normal tissue 82-86 . Specifically, these differences involve pathways crucial to cell proliferation, energy metabolism, and signal transduction 86 . The genetic profile of low grade astrocytomas shows most frequently alterations in p53 expression and in loss of heterozygosity on chromosome 17, which correlates with overexpression of...

Marrow Ablative Chemotherapy with Hematopoietic Stem Cell Rescue

Anna Butturini, Matthew Carabasi, and Jonathan L. Finlay ABSTRACT Marrow ablative chemotherapy with hematopoietic stem cell rescue (also referred to as hematopoietic stem cell transplantation) is a therapeutic strategy used to treat children and young adults with brain tumors whose conventional therapy is either too toxic (e.g., radiotherapy in infants) or ineffective (e.g., rhabdoid tumors or progressive malignant tumors). In this strategy, highdose chemotherapy (typically including alkylating...

Chemotherapy of Meningiomas

ABSTRACT Meningiomas are slow growing, extra-axial tumors that derive from the arachnoidal cap cells of the meninges. They comprise 1820 per cent of intracranial tumors and have an overall incidence of 2.6 per 100 000. Common presenting signs and symptoms include headache, hemiparesis, visual loss, seizures, gait difficulty, and confusion. Meningiomas are clearly delineated with enhanced computed tomography and magnetic resonance imaging scans. The main form of treatment for meningiomas is...

Chemotherapy of Pineal Parenchymal Tumors

ABSTRACT Pineal region tumors encompass a large group of neoplasms, including germ cell tumors, meningiomas, neuroectodermal tumors, and pineal parenchymal tumors (pineocytoma, pineoblastoma). They have an incidence of 0.3-0.7 per cent and usually affect patients between the ages of 20 and 35 years. Common presenting signs and symptoms include headache, Parinaud's syndrome, hydrocephalus, papilledema, and ataxia. Pineal tumors and hydro-cephalus are clearly delineated on enhanced magnetic...

Intrathecal Chemotherapy

Although the experience from systemic lymphoma and leukemia clearly supports the use of intrathecal chemotherapy to prevent or treat leptomeningeal disease, its role in the treatment of PCNSL remains controversial. Most therapeutic regimens for PCNSL rely on high-dose MTX and high-dose ARA-C, both of which, when administered as a rapid infusion, can achieve tumoricidal CSF levels, thus obviating the need for IT chemotherapy 41,46 . Furthermore, at least two retrospective studies have failed to...

Brain Tumor Models for Cancer Therapy

There are at least 18000 new cases of primary brain and CNS-malignant neoplasms diagnosed in the United States per year. The most common malignant CNS tumor is glioblastoma multiforme. The mean age of patients with glioblastoma multiforme is 52 years. These tumors cause approximately 12 000 deaths per year. Despite the relatively small numbers of CNS tumors, the morbidity and mortality they cause are significant 1,2 . Surgery remains the primary treatment for CNS tumors. After surgery, patients...

Chemotherapy of Medulloblastoma

ABSTRACT Medulloblastoma is the most common primary brain tumor in children and accounts for 25 per cent of newly diagnosed cases. Recent advances in treatment have extended 5-year survival rates from 3 to over 70 per cent during the past 50 years. These improvements in survival have resulted from a multi-modality approach that includes surgical resection, posterior fossa and craniospinal irradiation (RT), and chemotherapy for selected, high-risk patients. The literature regarding chemotherapy...

Clinical Presentation

The natural history of primary GCTs of the CNS has been established through a retrospective analysis of the literature, which selected 389 appropriate cases. Their histopathologic spectrum ranges from germinoma (65 per cent), teratoma (18 per cent), embryonal carcinoma (5 per cent), endodermal sinus tumor (7 per cent), to the most malevolent, the choriocarcinoma (5 per cent) 11,12 . Ninety-five per cent of primary intracranial GCTs originated adjacent to the III ventricle, along an axis from...

Natural Products

The vinca alkaloids, vincristine, and vinblastine, are derived from the periwinkle plant and function as cell-cycle-specific spindle poisons (see Figs. 2.6A,B) 8,21 . They enter cells via an energy dependent carrier-mediated transport system and bind to tubulin during S-phase, preventing polymerization and inducing metaphase arrest. Both the agents are water soluble, penetrate the blood-brain barrier poorly, undergo extensive metabolism in the liver, and are excreted primarily...

Practical Management

For cancer patients who require an AED, the selection of an appropriate AED must be based on effectiveness, side effect profile, cost, and available routes of administration. To add to this complicated decision-making, we must consider the potential for drug-drug interactions, particularly with CTAs. The ideal AED for neuro-oncology patients would have a long half-life to allow once daily dosing to improve compliance, would have a low incidence of tolerable or transient side effects, would be...

Surgery

Surgery is used in the treatment of NM for the placement of 1. intraventricular catheter and subgaleal reservoir for the administration of cytotoxic 2. ventriculoperitoneal shunt in patients with Drugs can be instilled into the subarachnoid space by lumbar puncture or via an intraventricular reservoir system. The latter is the preferred approach because it is simpler, more comfortable for the patient and safer than repeated lumbar punctures. It also results in a more uniform distribution of the...

Trials Dedicated To Ependymoma

Ten trials devoted solely to the treatment of patients with ependymoma have been reported over the years, and are presented here roughly in chronological order of their publication. Fifteen children younger than 18 months old with ependymoma were treated on a Children's Cancer Group (CCG) protocol with an eight-drug-in-one-day chemotherapeutic regimen (vincristine 0.05 mg kg, carmustine 7.25 mg kg, procarbazine 2.25 mg kg, hydroxyurea 45 mg kg, cisplatin 1.8 mg kg, cytar-abine 9 mg kg,...

Methylguanine Methyltransferase

One of the most important, and most studied mechanisms of resistance to alkylating agents is methylguanine methyltransferase (MGMT). The MGMT enzyme transfers the alkyl group from the O6 position of guanine to a cysteine residue in its active site. This repairs the DNA, prevents the formation of most additional secondary lesions, and causes irreversible inactivation of the MGMT molecule. Thus, MGMT-mediated resistance to alkylating agents is correlated to MGMT levels 17,48-52 . MGMT...

Gene Expression Patterns In Normal And Diseased Tissues

The gene expression profile of a cell gives insight into the mechanisms that lead to cell phenotype, function, and growth by helping to determine the levels of expression of regulatory genes, enzymes involved in biochemical pathways, and other clues to cellular function. One of the most attractive applications of microarrays is to study the differential pattern of gene expression in normal versus diseased tissues in order to identify potential targets for therapy. The first generation of...

Chemotherapy of High Grade Astrocytomas

ABSTRACT High-grade astrocytomas, including anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM), are frequently diagnosed tumors that continue to have a poor prognosis and protracted survival. Chemotherapy has recently been demonstrated to provide a survival benefit in patients with AA and GBM, in addition to surgical resection and irradiation, by several meta-analyses. The improvement in survival has been modest and mainly associated with the use of nitrosourea drugs such as BCNU and...

Pineal Anatomy And Physiology

The pineal gland has been a topic of intense interest since antiquity, and yet its function remains somewhat obscure 1,2 . The average gland is 7.4 mm in length, 6.9 mm in width, and 2.5 mm thick 3 . It is surrounded by a capsule and is composed of lobules separated by connective tissue septae. The gland forms during the seventh week of embryonic development, when the roof plate of the primitive diencephalon thickens medially and then evaginates posteriorly. In the adult, the pineal gland is...

Drug Movement Across The Bbb And Determinants Of Cns Drug Concentration

The factors acting to determine the concentrations of drugs and other molecules at a particular location within the CNS are complex. As with other cell membranes, the cerebral endothelium is permeable to low molecular weight (< 500-600 Da), nonpolar, lipid-soluble molecules such as oxygen, carbon dioxide, ethanol, nicotine, diazepam and anesthetics 19,29 . For small molecules, a good correlation exists between the lipophilicity or lipid solubility of a drug (i.e. hydrophobicity), as...

Other Small Molecule Egfr Inhibitors

Although studies with Iressa are perhaps furthest along, a number of other small molecule inhibitors of EGFR are currently or soon to begin clinical trials in patients with brain tumors. OSI-774 (Erlotinib, Tarceva, Genentech, South San Francisco, CA) exhibits reversible inhibition of EGFR, by competition with the ATP-binding site, similar to ZD1839, with a median inhibitory concentration in the low nanomolar range 132,180 . This agent inhibits EGFR autophosphory-lation at concentrations in the...

Clinical Pharmacology of Brain Tumor Chemotherapy

ABSTRACT Chemotherapy has become a more common adjunctive treatment for most patients with malignant brain tumors and for selected patients with benign neoplasms. In general, the most effective chemotherapeutic drugs are alkylating agents, such as the nitrosoureas, procarbazine, temozolomide, cisplatin, carboplatin, and cyclophosphamide. Other agents that have been applied to brain tumors include methotrexate, vincristine, etoposide, irinotecan, hydroxyurea, and paclitaxel. Molecular...

Matricellular Proteins

As discussed previously, designing therapeutic peptides to circumvent these proteins may be difficult. To date, the only matricellular protein target taken to clinical trial is Tenascin-C. After demonstrating that anti-tenascin monoclonal antibody 81C6 exhibited therapeutic potential in s.c. and intracranial human xenografts in athymic mice, a study demonstrated that the 131I-labeled antibody demonstrated selective intracranial localization 161 . Currently, a clinical study assessing the...

Info

Herpes Sufferers Singles

FIGURE 18.1 The two-compartment model. Carboplatin (carbo) is administered intra-arterially immediately after osmotic disruption of the BBB with hypertonic mannitol. (A) shows delivery of carboplatin across the BBB. Sodium thiosulfate (STS) is administered intravenously 4 (or 4 and 8) h after osmotic disruption, after BBB permeability has returned to baseline levels. (B) shows exclusion of STS from the brain. FIGURE 18.1 The two-compartment model. Carboplatin (carbo) is administered...

Chemotherapy

Chemotherapy is the only treatment modality that can treat the entire neuraxis. Chemotherapy may be administered systemically or intrathecally 41-45, 165-170 . Intrathecal chemotherapy is the mainstay of treatment for NM in patients with solid tumors 41-45 . Retrospective analysis or comparison to historical series suggest that the administration of chemotherapy to the CSF improves the outcome of patients with NM and solid tumors. However, it is noted that most series will exclude patients that...

Clinical Bbbd Results

Since the goal of BBBD is enhanced delivery to the CNS, while preserving patient's neurocognitive functioning and quality of life, BBBD clinical protocols include an extensive neuropsychological test battery and quality of life questionnaire, which are completed at study entry and at follow-up. Excellent results have been obtained in patients with PCNSL, a highly chemosensitive tumor, using BBBD-enhanced delivery of methotrexate-based chemotherapy. It is well known that the prognosis for...

Anaplastic Oligodendroglioma

In 1988, Cairncross and Macdonald 7 described eight consecutive patients with recurrent aggressive oligodendroglioma who durably responded to nitrosurea-based chemotherapy. Six of these patients were treated with PCV, a treatment regimen first described by Levin et al. 28 . PCV chemotherapy has subsequently been studied as first-line, second-line, adjuvant, and neoadjuvant (pre-radiation) therapy. Standard dose PCV is given at a frequency of once every eight weeks. CCNU is given by mouth at a...

The Hypoxic Tumor Microenvironment And Hif Activation

Tumor growth and progression occurs as a result of cumulative acquisition of genetic alterations affecting oncogenes or tumor suppressor genes selecting for tumor cell clones with enhanced proliferation and survival potential. However, high proliferating tumors frequently outstrip their vascular supply leading to a tumor microenvironment characterized by low oxygen tension, low glucose levels, and an acidic pH. Hypoxia is a common feature of solid tumor growth. Reduced pO2 levels have been...

Concomitant Chemotherapy And Irradiation Approaches

Overall, radiation therapy remains the most effective form of treatment for newly diagnosed highgrade astrocytomas and many other solid tumors 12-14 . Intensive research activity has led to an improved understanding of the cellular and molecular basis for radiation sensitivity and radioresistance 40 . In parallel to this research effort, many investigators have begun to evaluate agents with the ability to enhance the therapeutic effect of irradiation, while minimizing additional toxicity 41 ....

Chemotherapy and Anti Epileptic Drug Interactions

ABSTRACT Patients with primary or metastatic brain tumors are often on medications that alter the pharmacokinetics of chemotherapeutic agents (CTAs). The most common drugs administered to neuro-oncology patients that can affect their chemotherapy are anti-epileptic drugs (AEDs). Oncology patients who require chemotherapy may also be on AEDs for pre-existing epilepsy, neuropathic pain or headaches. These enzyme-inducing anti-epiletic drugs (EIAEDs) induce the production and activity of hepatic...

Blood Brain Barrier Disruption Chemotherapy

Murillo, and Edward A. Neuwelt ABSTRACT The goal of chemotherapy administered in conjunction with blood-brain barrier disruption (BBBD) is maximizing drug delivery to the brain, while preserving neurocognitive function and minimizing systemic toxicity. Translational blood-brain barrier (BBB) pre-clinical and clinical studies at Oregon Health & Science University (OHSU) evaluate the toxicity and antitumor efficacy of chemothera-peutics, chemoprotectants, and...

Clinical Presentation And Prognostic Factors

The majority of patients with metastatic brain tumors develop one or more progressive symptoms that are caused by enlargement of the mass within the brain. Although virtually any symptom is possible, depending on the location of the MBT, the most frequent complaints include headache (25-40 per cent), alterations of thinking and memory (20-25 per cent), focal weakness (20-30 per cent), and seizure activity (15-20 per cent) 1,3-5 . Less common symptoms consist of gait difficulty (15 per cent),...

Ia Chemotherapy For Primary Cns Lymphoma

Primary CNS lymphoma (PCNSL) has been shown to be a chemosensitive tumor, and can respond well to multi-agent chemotherapy, including methotrexate-based or carboplatin-based IA regimens 5,6,78,79 . In the majority of cases, IA chemotherapy for PCNSL is used in combination with IA mannitol and blood-brain barrier disruption, to further improve delivery of chemotherapy drugs to tumor cells 5,79,80 . Many patients are also treated ''up-front'', before any form of irradiation. The median survival...

Deregulation Of Apoptotic Pathways In Brain Tumors

Alterations of specific components of the cell death machinery are highly relevant for both tumorigenesis and resistance to therapy. Selective pressures for apoptosis-deficient clones are apparent already at early stages of tumorigenesis. One major proapoptotic stress is hypoxia. Recent progress in the understanding of tumor evolution has demonstrated an initial stage of vessel cooption followed by regression, leading to a secondarily avascular tumor and massive tumor cell loss 9 . Ultimately,...

Practical Effects Of Aedchemotherapy Interactions

Effects on Clinical Trial Design in Neuro-Oncology The potential for subtherapeutic chemotherapy dosing in patients on EIAEDs has affected clinical trial design for patients with malignant gliomas, and should also be taken into account in trials for patients with central nervous system metastases as well. Clinical trials for patients with brain tumors must stratify patients by the use or non-use of EIAEDs, and seek separate maximum tolerated doses for any CTA that might be metabolized by the...

Apoptosis Pathways and Chemotherapy

Steinbach and Michael Weller ABSTRACT Tumor cell death is the ultimate goal of chemotherapy. In particular, the induction of apoptosis has been suggested as a strategy for efficient and selective elimination of tumor cells. However, in malignant gliomas, the most common malignant intrinsic brain tumors, there is little evidence that the currently available chemotherapeu-tic drugs mediate their effects via induction of apoptosis, with the possible exception of anaplastic...

Conclusions

Drug interactions between AEDs and CTAs have become increasingly recognized. Induction of the hepatic cytochrome P-450 enzyme system by EIAEDs increases the rate of clearance of some CTAs, resulting in decreased and potentially subtherapeutic CTA plasma concentrations unless the CTA dose is increased. Increasing the CTA dose to overcome this effect substantially increases the cost of treatment, and also increases the potential for toxicities and adverse side effects, particularly if the EIAED...

Drug Selection

Many brain tumor patients take antiepileptic drugs (AED) for seizure prophylaxis. Some anticonvulsants may induce the hepatic cytochrome P450 system and alter the metabolism of a treatment agent being studied 17 . Such drug interactions may alter the type and severity of toxicity that patients experience. For example, it has been discovered that patients taking paclitaxel or CPT-11 while taking enzyme-inducing antiepileptic drugs (EIAED) may have lower-than-expected plasma levels and...

Chemotherapy Of Infants And Very Young Children

The developing nervous system of infants and very young children (newborn to 3 years) is highly sensitive to the effects of irradiation 12,14,29-31 . More than 60 per cent of surviving brain tumor patients will develop significant cognitive impairment after exposure to cranial RT. In this group of medulloblastoma patients (roughly 20 per cent of all pediatric cases, which also have the poorest prognosis for survival), chemotherapy has a very prominent role, because it is often applied ''up...

Dysplastic Gangliocytoma Of The Cerebellum

Dysplastic gangliocytoma of the cerebellum (WHO grade I), also known as Lhermitte-Duclos disease, is a rare hamartomatous or non-neoplastic tumor of the cerebellar cortex that most commonly presents with increased intracranial pressure and hydrocephalus, headache, cerebellar symptoms, and cranial nerve palsies 73,74 . It usually presents in the third or fourth decade with no gender predominance 73,74 . Recently this condition has been noted to occur in association with Cowden disease, one of...

Animal Studies

An extensive number of animal studies have established the safety and efficacy of convective delivery to normal brain such that calling it a novel technique, presently, is difficult. Trials have been performed in cats, rats, non-human primates, and pigs (unpublished data) 14-31 . Once anesthetized, the animal's head is secured and the cannula is placed with stereotactic guidance. Popular sites of infusion include the corona radiata, the striatum, and the brainstem 14,17,18,24,25,27,28,32 ....

Physiologic And Pathological Barriers To Antineoplastics In The

The unique physiological and pathological barriers encountered in the central nervous system impede drug delivery for the treatment of brain lesions. Oral and intravenous injections of chemotherapeutics have difficulty reaching therapeutic concentrations at brain tumor sites because of these barriers, including the blood-brain barrier (BBB), blood-cerebrospinal fluid barrier (BCB), and blood-tumor barrier (BTB) 5 . The BBB is formed from tight junctions between cerebral capillary endothelial...

Predictive Modeling Of Therapeutic Vulnerability Of Brain Tumors

Partly due to their heterogenic nature and early tendency to actively invade the surrounding brain parenchyma, glial tumors represent an intractable disease. All the current treatment strategies are derived from clinical trials comparing varieties of insufficient therapies prone to fail since tumor cells are not being specifically targeted. With the exception of LOH 1p 19q as predictor for increased sensitivity to chemotherapy in oligodendroglioma, no markers exist for allowing treatment...

Preclinical Studies Of Thiol Chemoprotection

Chemotherapy dose intensive strategies for the treatment of malignant brain tumors necessitate minimizing CNS and systemic toxicities. Carboplatin has shown efficacy in malignant brain tumors 23 . However, carboplatin causes myelosuppression including severe thrombocytopenia, often requiring platelet transfusions and dose reductions of subsequent carboplatin treatments. In addition, when administered in conjunction with BBBD, carboplatin causes irreversible hearing loss in a large proportion of...

Topoisomerase Inhibitors

Etoposide is a natural product that derives from podophyllotoxin (see Fig. 2.11). Its mechanism of action is to cause single-strand and double-strand breaks in DNA through interaction with DNA topoisomerase II, inducing arrest in the G2-phase of the cell cycle 8,21,154 . This activity is mediated through the formation of a stable complex with DNA and topoisomerase II. In addition, etopo-side binds to tubulin and inhibits microtubular assembly. Although etoposide is highly...

ATPBinding Cassette or Multidrug Resistance Genes

The ATP-binding cassette (ABC) genes are a family of genes that encode proteins involved in multi-drug resistance in a number of cancers. These proteins reside in membranes and act as efflux pumps, removing toxic compounds from the cell. They are not thought to be involved in resistance to alkylating agents however, they are involved in resistance to the topoisomerase inhibitors VP-16 (etoposide) and CPT-11 (irinotecan), as well as vincristine. Specifically, ABCB1 (or MDR1) encodes...

Combination Ia Chemotherapy Of Recurrent Gliomas

IA chemotherapy approaches utilizing multiple IA agents or the combination of an IA agent with an oral or intravenous drug have also been extensively reported in the literature (see Table 17.4). The majority of regimens have focused on the use of IA carmustine in combination with other drugs. The initial experience was reported by West and colleagues, when they utilized a regimen of IA carmustine (100 mg m2) plus PCV for nine patients with recurrent malignant gliomas 46 . The objective response...

Toxicity Of Ia Chemotherapy

The most common toxicity of patients receiving IA chemotherapy is ipsilateral periorbital erythralgia and visual loss, which in many cases can be dose-limiting 4-7,85,86 . Ophthalmological examination of affected patients suggests a toxic retinal vasculitis, with retinal arteriolar narrowing, hemorrhages, nerve fiber layer infarctions, and arterial phase leaks 31 . An anterior ischemic optic neuropathy may also occur in some patients 58 . The incidence of visual loss among the cases cited in...

Handbook of Brain TUmor Chemotherapy

Abrey (395) Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Till Acker (219) Karolinska Institute, CMB, Stockholm, Sweden Eric Amundson (274) Department of Neurological Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Kaveh Asadi-Moghaddam (332) Department of Neurological Surgery, The Ohio State University Medical Center, Columbus, OH, USA Michael E. Berens (115) TGen, The Translational Genomics Research Institute,...

Local Delivery In Rat Brain Tumor Models

Gene therapy remains very attractive as a treatment strategy for brain tumors since local delivery is feasible and likely to have a major impact on the disease 19, 20 . Several gene therapy approaches are based upon prodrug-activating enzymes, inhibition of tumor neovascularization, and stimulation of antitumor immune responses. The most widely explored paradigm is based on the activation of ganciclovir to a cytotoxic compound by a viral enzyme, thymidine kinase, which is expressed by tumor...

Neuroimaging

Plain radiographs and angiographic evaluation of meningiomas have mainly been supplanted by computerized axial tomography (CT), magnetic resonance imaging (MRI), and MR angiography (MRA) 1,2,39 . Plain radiographs can show calcified tumors and regions of hyperostotic bone. Angiography may be helpful for the evaluation of the safety and feasibility of preoperative embolization of highly vascular meningiomas 40 . Angiography is able to demonstrate the main arterial blood supply and also clearly...

Radiotherapy

Radiotherapy is used in the treatment of NM for 1. palliation of symptoms, such as a cauda equina syndrome, 2. to decrease bulky disease such as co-existent parenchymal brain metastases, and 3. to correct CSF flow abnormalities demonstrated by radionuclide ventriculography. Patients may have significant symptoms without radiographic evidence of bulky disease and still benefit from radiation. For example, patients with low back pain and leg weakness should be considered for radiation to the...

Glutathione Stransferase

In addition to DNA repair, resistance to alkylating agents and other therapies can come about through detoxification. The family of glutathione-S-transferase (GST) enzymes catalyze the conjugation of electro-philic compounds with glutathione. These include various carcinogens, chemotherapeutic agents, and their metabolites 97,128-134 . There are 5 families of GSTs a(GSTA), m(GSTM), p(GSTP), 9(GSTT) and Z(GSTZ) 130,131 . Earlier work demonstrated the importance of the GSTP, GSTM, and GSTT...

Immunological Approaches In Rat Brain Tumor Models

The tolerance of the central nervous system (CNS) for activated host immune reactions indicates that the effects of immunotherapy might be decreased for brain tumors. Iwadate et al., 35 developed an interleukin-2 producing 9L rat gliosarcoma and assessed the effect of secretion of interleukin-2 on the growth and immunological responses to the tumor implanted subcutaneously and intracranially. The Fischer 344 rats rejected the 9L IL-2 tumors when implanted subcutaneously however, the same tumors...

Future Directions

Presently different experimental approaches are taken to study individual features of a complex disease such as brain tumors. It is, however, not a single gene or protein that is the ultimate driver and origin of a malignant disease but rather a variety of complex networks of closely interacting proteins providing alternate interchangeable routes for maintenance and progression of autonomous growth. It is therefore imperative to integrate data sets (i.e., genetic, genomic, and proteomic)...

Supportive Therapeutics

Supportive treatment of brain tumor patients is primarily concerned with controlling the symptoms caused by elevated intracranial pressure and minimizing seizure activity 1,2 . The use of other medications to ameliorate symptoms, such as nausea and emesis (i.e., secondary to edema or chemotherapy), constipation, pain, anxiety, and depresssion are beyond the scope of this chapter but are summarized in recent review articles 14-20 . Corticosteroids. The use of corticosteroids is often necessary...

Glioma

The management of patients with gliomas and leptomeningeal gliomatosis (LG) is particularly challenging in that the majority of patients have compromised neurological function resulting both from the treatment and topography of their primary tumor 33-40 . The majority of studies regarding LG are primarily autopsy based 33-40 . Erlich and Davis performed an autopsy study of 25 patients with GBM, amongst whom 20 spinal cord examinations were performed 33 . Five of these patients (25 per cent) had...

References

C., and Shapiro, J. R. (1995). Cytogenetic and flow cytometry, DNA analysis of regional heterogeneity in a low grade glioma. Cancer Res 55, 1569-1577. 2. Scheck, A. C., Shapiro, J. R., Coons, S. W., Norman, S. A., and Johnson, P. C. (1996). Biological and molecular analysis of a low grade recurrence of a glioblastoma multiforme. Clin Cancer Res 2, 187-199. 3. Scheck, A. C., Shapiro, J. R., Ballacer, C. et al. (1996). Clonal analysis of human malignant glioma cells...

Current Therapeutic Management Strategies for Primary Intracranial Germ Cell Tumors

ABSTRACT Two factors appear dominant in determining the prognosis of children and adolescents with primary intracranial germ cell tumors (GCT) histological diagnosis and the extent of disease dissemination. Germinoma is associated with significantly longer survival than the nongerminatous germ cell tumors (NG-GCT), which often fail conventional treatment. Consensus exists for managing germinomas, without evident dissemination, with involved field external beam radiotherapy (EBRT). The long-term...

Cerebellar Liponeurocytoma

First recognized by Bechtel et al. in 1978 6 , this is a well-differentiated neurocytic tumor (WHO grade I or II) that occurs in the fifth and six decades 75 . They occur in the cerebellum and present with symptoms referable to the posterior fossa, similar to dysplastic gangliogliocytoma of the cerebellum. They contain round neoplastic cells with a consistent neuronal and focal lipomatous differentiation and a low rate of proliferation. There is focal GFAP expression and also NSE and...

Cn

Bn, Br, Mu, Colon, Bn, Ma, Lv, Ov, Pla, S, Pa, MG, Te, E molecular targets TABLE 14.2 (Continued) Cell surface proteoglycan Hyaluronan receptor factor, fibrinogen ICAM-1, ICAM-2, ICAM-3 von Willebrand's factor VN, FN, CN, TN, OPN, TSP, von Willebrand's factor, PECAM-1, fibrinogen, human L1 LN CS, DS, FGF-2, PDGF-AA Hyal, ankyrin, FN, MIPl , OPN (act) myeloid B lymph, NK cells, macro, micro Myeloid, dendridic cells, (act) B lymph, macro, micro (act) B & T lymph, EC, mono, glia, Schwann cells...

Therapeutic Implications

The marked chemotherapy and radiation resistance of gliomas has focused attention on the means by which signaling aberrations underlying gliomagenesis contribute to resistance to cell death. In this regard, the PI3-kinase pathway is recognized for supporting cellular proliferation and survival, thereby promoting both malignant transformation and resistance to therapy. Several lines of investigation identify PI3-kinase as a regulator of cellular responses to ionizing radiation. Biochemical...

Local Delivery In Human Brain Tumor Xenograft Models

The Escherichia coli gpt gene sensitizes cell expressing the gene to the prodrug 6-thioxanthine (6TX) 64 . Rat C6 glioma cells were infected with a retrovirus vector that transduces the E. coli gpt gene and a clonal cell line designed C6GPT-7 was derived. In vivo both 6-thioxanthine and 6-thioguanine inhibited the growth of subcutaneously transplanted C6GPT-7 cells but not C6 parental cells in nude mice. In an intracerebral model, both 6-thioxanthine and 6-thioguanine exhibited...

Pcv And Oligodendro

The use of procarbazine, lomustine CCNU , and vincristine (PCV) was first described by Levin et al. and has been since studied as first-line, second-line, adjuvant, and neoadjuvant (pre-radiation) therapy in the treatment of malignant gliomas 37 . The landmark papers of Cairncross and Macdonald describing the unique chemosensitivity of oligodendrogliomas, most treated with PCV, did not include oligoastrocy-tomas 14,15 . These and other reports prompted the study of this regimen in...

Acknowledgment

Alex Merrick, PhD, for his assistance in writing the sections of this manuscript concerning drug metabolism and resistance. Dr. Merrick is Head, Proteomics Group, National Center for Toxicogenomics, NIEHS. I also acknowledge the valuable input from Paul Van Ness, M.D at the University of Texas Southwestern Medical Center in Dallas for his comments regarding practical 1. Cohen, N., Strauss, G., Lew, R., Silver, D., and Recht, L. (1988). Should prophylactic anticonvulsants be...

Molecular Genetics of Brain TumorsAn Overview

ABSTRACT Human brain tumors continue to benefit from ongoing investigation of the molecular genetic changes that explain gliomagenesis, malignant progression, patient outcome, and possibly therapeutic responsiveness. Optimal utilization of current therapies may be gained by using molecular genetic markers of glial tumors, but meaningful advances in improved patient treatment will emerge from new therapies matched to the specific chemo-vulnerabilities of these tumors as addressed by...

Adjuvant Chemotherapy Approaches

Many different chemotherapy drugs have been used in the adjuvant setting for high-grade astro-cytomas, including the nitrosoureas, as outlined above. The vast majority of these drugs have either been ineffective or unable to demonstrate a clinical advantage (i.e., prolonged survival or TTP) over standard intravenous BCNU 20-24 . This conclusion has been further corroborated by a recent randomized phase III trial of irradiation plus adjuvant PCV versus radiation therapy alone for patients with...

Multilevel Dysregulation Of Pi3kinase Implications For Gliomagenesis

Constitutively activated PI3-kinase, PKB Akt, and mTOR appear to contribute, within select backgrounds, to the development of high-grade gliomas. Dysregulation of PI3-kinase occurs through several of the most commonly observed genetic aberrations in malignant gliomas. These include loss of PTEN and amplification or overexpression of growth factor receptors, such as PDGFR and EGFR. PTEN loss has been described in several solid tumors, notably glioblastoma multiforme and endo-metrial and prostate...

Temozolomide

Temozolomide (Temodar) is an imidazotetrazine derivative of the alkylating agent dacarbazine with activity against systemic and CNS malignancies 25,58-60 . The drug undergoes chemical conversion at physiological pH to the active species (MTIC). Temo-zolomide exhibits schedule dependent antineoplastic activity by interfering with DNA replication through the process of methylation. The methylation of DNA is dependent upon formation of a reactive methyl-diazonium cation, which interacts with DNA...

Interstitial Chemotherapy and Polymer Drug Delivery

Haque, Eric Amundson, Michael Dorsi, and Henry Brem ABSTRACT Malignancies of the central nervous system represent a formidable challenge and prognosis of patients remains dismal. Physiological barriers impede efficacious delivery of tumoricidal concentrations of anti-neoplastic agents to the CNS without incurring undesirable systemic toxicities. The development of local delivery devices for controlled administration of chemotherapeutics provides a new mechanism to effectively treat...

Gcd

Adhesion molecules, molecular target cell-cell, 205-207 cadherins, 196, 200, 205, 207 Ig-superfamily, 196, 200, 205-207 selectins, 201, 203, 205 cell-ECM, 205-207 cell-surface proteoglycans, 206 integrins, 206-209, 211, 212 Alkylating chemotherapy agents, resistance mechanisms detoxification ATP-binding cassette (ABC) genes, 96 drug resistance, in vitro analysis, 96 glutathione-S-transferase (GST) enzymes, isoforms, 95 metallothioneins (MT), isoforms, 95, 96 DNA mammalian mismatch repair (MMR)...

Acknowledgments

The author would like to thank Ryan Smith for research assistance. Dr. Newton was supported in part by National Cancer Institute grant, CA 16058 and the Dardinger Neuro-Oncology Center Endowment Fund. 1. Newton, H. B. (1994). Primary brain tumors Review of etiology, diagnosis, and treatment. Am Fam Physician 49, 787-797. 2. Preston-Martin, S. (1996). Epidemiology of primary CNS neoplasms. Neurol Clin 14, 273-290. 3. Davis, F. G., and McCarthy, B. J., (2001). Current epidemiological trends and...

Temozolomide Glioma

Brain With Brain Cancer Tumor

A., Smith, M. A. et al. (1999). Cancer surveillance series corrected Brain and other central nervous system cancers Recent trends in incidence and mortality. J Natl Cancer Inst 91, 1382-1390. 2. Guha, A., Dashner, K., Black, P. M., Wagner, J. A., Stiles C. D. (1995). Expression of pdgf and pdgf receptors in human astrocytoma operation specimens supports the existence of an autocrine loop. Int J Cancer 60, 168-173. 3. Parker, S. L., Tong, T., Bolden S., Wingo, P. A....

Clinical Presentation And Imaging Findings

Common presenting symptoms of LGA include seizures, headache, altered mental status, and focal neurological deficit. Seizures are the presenting symptom in more than 50 per cent of all cases 12,13 . Headache and focal neurological deficit occur less frequently, and signs of raised intracranial pressure are uncommon 12 . Magnetic resonance imaging (MRI) is the most sensitive test available to diagnose LGA. The tumor typically appears as a low-intensity area on T1-weighted images, whereas there...

What Is Bystander Effect In 5-fu

FIGURE 23.1 Herpes simplex virus thymidine kinase HSVtk ganciclovir GCV , monophosphate MP triphosphate TP . in culture and in vivo 20 . Possible explanations for radiation enhancement is that DNA which has incorporated acyclovir may be susceptible to radiation-induced strand breakage, and or acyclovir might sensitize cells by inhibiting polymerase activity required for the repair of radiation-induced DNA damage. Several strategies have been developed in attempting to improve tumor cell...

Oh

Dibromodulcitol is administered orally and undergoes rapid and complete absorption from the gastrointestinal tract 167 . The first use of dibromodulcitol was as a sensitizer during radiation therapy of malignant gliomas 168 . Studies of single-agent dibromodulcitol have demonstrated activity against a variety of PBT 169,170 . Levin and colleagues administered dibromodulcitol 100-150 mg m2 per day to patients with recurrent PBT and noted moderate efficacy in...

Ganglioglioma And Gangliocytoma

Perkins named this entity in 1926 1 . Ganglioglio-mas WHO grade I or II, some grade III and IV lesions make up 1.3 per cent of all brain tumors and contain both neuronal and glial elements, while gangliocytomas WHO grade I are composed predominantly of neoplastic neurons 26 . They typically present with seizures because of their predilection for the temporal lobe. They usually present before the age of 30 with a male female ratio of 1-2 1 27 . Imaging on CT scan with contrast shows a solid mass...

Optic Pathway Hypothalamic Gliomas

Optic pathway gliomas hypothalamic gliomas OPHG represent about five percent of intracranial neoplasms in young children. Children with these tumors tend to have an excellent long-term prognosis, and long-term survival is estimated at about 85 per cent 1,14 . Patients with optic pathway tumors are generally diagnosed on neuroimaging after presenting with decreased vision, optic atrophy, proptosis, or nystagmus. Optic gliomas are also the most common tumor associated with Neurofibromatosis Type...

Bloodbrain Barrier In Rat Brain Tumor Models

The blood-brain barrier remains a very active area of investigation even though the blood-brain tumor barrier is more permeable than the blood-brain barrier. There is still significantly decreased delivery of anticancer drugs to brain tumors. The endothelial cells that form the vasculature of the tumor express protein markers that are absent or expressed at very low levels in the normal brain endothelium. Ningaraj et al., 15 found the calcium-dependent potassium K Ca channel is increased in...

Pathology Of Tumors Of The Meninges

Pictures Meningioma Tumor

Tumors of the meninges comprise a large and diverse group of neoplasms that mostly have menin-gothelial or mesenchymal, non-meningothelial origins see Table 1.9 24,25 . The most common primary tumor of this group is the meningioma 18-20 per cent of intracranial tumors , which has meningothelial cell origins and is composed of neoplastic arachnoidal cap cells of the arachnoidal villi and granulations. Meningiomas can occur anywhere within the intra-cranial cavity, but favor the sagittal area...

Clinical Studies Of Thiol Chemoprotection

Clinical studies have shown hearing protection when high-dose STS 16-20 g m2 was administered as part of a two-compartment model in patients with malignant brain tumors 24,25 . That is, carboplatin was administered intra-arterially immediately after BBBD. High-dose STS was administered intravenously in a delayed fashion, 4 or 4 and 8 h after carboplatin, thus providing spatial and temporal TABLE 18.2 Per cent Patients and Per cent Carboplatin Courses with Platelet Nadir Less than 20 x 10 mm ,...

Pathology Of Intracranial Germ Cell Tumors

Primary intracranial germ cell tumors are rare neoplasms that typically affect children and teenagers. TABLE 1.10 WHO Classification Intracranial Germ Cell Tumors Germinoma Embryonal carcinoma Yolk sac tumor Choriocarcinoma Teratoma Mature Immature Teratoma with malignant transformation Mixed germ cell tumors They are analogous to their gonadal and extragonadal systemic counterparts and arise almost exclusively in the midline, affecting the pineal and sellar regions, third ventricle, and...

Bloodbrain Barrier In Human Brain Tumor Xenograft Models

Even though the blood-brain tumor barrier BTB is more permeable than the blood-brain barrier BBB , the blood-brain tumor barrier still significantly restricts the delivery of anticancer drugs to brain tumors. Ningaraj et al., 15 were able to modulate the calcium-dependent potassium K Ca channel using a specific K Ca channel agonist, NS-1619, to obtain sustained enhancement of selective drug delivery in xenograft brain tumor models. NS-1619 administration was used to increase delivery of...

Chemotherapy of Ependymoma

ABSTRACT Ependymomas are rare neoplasms of the central nervous system CNS seen most commonly in children. The most effective treatment modality is surgical resection, and it is widely held that gross total removal of these tumors confers a better prognosis. Radiation therapy RT is commonly used to treat residual, recurrent, or progressive disease. The experience with chemotherapy has been a long and frustrating one, both up front and at relapse. Certainly, significant radiographic and clinical...

The Normal Bloodbrain Barrier Ultrastructural And Cellular Considerations

The blood-brain barrier BBB was discovered by Paul Ehrlich in 1885 when he noted that dye injected into the bloodstream of a rabbit stained almost every bodily organ, but not the brain and spinal cord 1,2 . Intravascular dye introduction will also cause staining of the dura, but not affect the underlying lepto-meninges or CSF 3,4 . At the cellular level, the BBB is composed of a continuous layer of endothelial cells, which constitutes the luminal surface of more than 99 per cent of the...

Gliomas

The benefit of adding conventional-dose chemotherapy to surgical resection and irradiation in supratentorial malignant or high-grade gliomas e.g., anaplastic astrocytoma and glioblastoma multiforme is modest see Chapter 24 . A recent meta-analysis reported a better outcome in patients who received both chemotherapy and irradiation 48 . Most recently, the administration of temozolomide concurrent with and following irradiation for adults with high grade gliomas appears to be producing promising...

Biology And Molecular Genetics

Significant progress has been made in the understanding of the biology and molecular genetics of meningiomas 1-3,20-22 . The tumors are thought to arise from malignant transformation of arachnoidal cap cells, which are meningothelial cells with both mesenchymal e.g., spindle cell morphology, collagenous stroma and epithelial e.g., numerous intercellular junctions, expression of epithelial membrane antigen features. Arachnoidal cap cells form the outer layer of the arachnoid mater and arachnoid...

Herpes Simplex Virus Type 1 Thymidine Kinase HSVtk Ganciclovir

The herpes simplex virus type 1 thymidine kinase enzyme HSVtk approach is the most widely studied suicide gene strategy. The HSVtk system was developed in 1986 6 , and was the first approach used in patients with malignant brain tumors in 1992 7 . This approach has been conducted in combination with guanosine-based prodrugs, such as ganciclovir GCV and acyclovir, which were originally developed as antiviral agents 8 . These prodrugs are nontoxic nucleoside analogs, which are converted by HSVtk...

The Bloodbrain Tumor Barrier Effect Of Tumors On The

Brain Tumor Images Mri

The capillary endothelium within brain tumors has sometimes been called the ''blood-brain tumor barrier'' 2,33 . Clinically, the permeability of this endothelium and degree of vascularity is indicated by the degree of tumor enhancement on CT and or MRI scans. Meningiomas and brain metastases, as examples, would not be expected to have a true BBB, at least by the time they are visible by current neuroimaging studies. Most of the blood supply of meningiomas is derived from the dura neither...

DNA Mismatch Repair

Depletion of MGMT activity by promoter methylation or the use of inhibitors is not always sufficient to ensure alkylating agent sensitivity 52 . In the absence of functional MGMT, an important additional mechanism of resistance to alkylating agents is DNA mismatch repair MMR deficiency. At least 5 proteins organized as heterodimers are involved in MMR MutSa a heterodimer of hMSH2 and hMSH6 , MutSp a heterodimer of hMSH2 and hMSH3 and MutLa a heterodimer of hMLHl and hPMS2 . Mismatched...

Development Of Polymerbased Local Delivery Systems

Controlled drug delivery of macromolecules utilizing implantable polymers was first described in 1976. Langer and Folkman introduced a novel method of sustained release of macromolecules from an ethylene vinyl acetate copolymer EVAc 34 . Using first order kinetics, this non-biodegradable polymer releases therapeutic agents by diffusion Fig. 19.3A , based on the properties of the bound agent, including molecular weight, electrostatic charge, and liposolubility. Although EVAc polymers have proven...

E7070 a Sulfonamide

E7070 has been shown to target the G1 phase of the cell cycle 166 . Inhibition of G1 S transition is achieved by blocking the activation of both CDK2 and cyclin E. This synthetic sulfonamide has been developed for use in clinical trials for the treatment of solid tumors including those of the colon and lung. Phase I trials with E7070 evaluated different treatment regimens including combination therapy with irinotecan http www.clinicaltrials.gov identifier NCT00060567 167 . While administration...

Delivery Systems And Strategies For Brain Tumor Targeted Delivery

Several approaches have been implemented to address the limitations presented by both the natural and pathologic barriers in the CNS. The strategies used to bypass these boundaries can be divided into chemical and physical based techniques 7 . Chemical strategies focus on improving drug delivery by altering the structure of the drug or by disrupting the BBB. Physically based techniques include 1 catheter, 2 convection-enhanced delivery, and 3 polymer or microchip systems which directly release...

Nucleotide and Base Excision Repair

Tmz Base Excision Repair

DNA damage that causes a distortion in the shape of the DNA helix such as those caused by intrastrand dimers can be repaired by nucleotide excision repair NER 120-122 Fig. 6.3 . There are many polypep-tides involved in this repair system for review see 18,122 . The DNA lesion is recognized by a polypeptide complex and a 27-29 nucleotide long region around the lesion is removed. The gap is then filled by a complex of DNA replication proteins and the repaired region is ligated to complete the...

Summary

The events of the cell division cycle can be summarized as follows the G1 cyclins prepare the chromosomes for replication via interactions with corresponding CDKs. A consequent increase in S-phase promoting factors prepares the cell to enter S-phase and duplicate its DNA. As replication continues, one of the cyclins shared by both the G1- and the S-phase CDKs, cyclin E, is destroyed and an increase in M-phase cyclins cyclins A, B ensues. M-phase-promoting factors such as cyclins A and B and...

Chemotherapy In Human Brain Tumor Xenograft Models

The efficacy of protracted schedules of therapy of the topoisomerase I inhibitors topotecan and irinotecan CPT-11 were evaluated against a panel of human tumor xenografts 75 . Both agents demonstrated good activity against brain tumor xenografts with irinotecan causing complete regressions in 2 of 3 lines and topotecan inducing complete regressions in 1 of 3 lines. The results indicate that low-dose protracted schedules of daily administration of these topoisomerase I inhibitors is either...