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...

Info

Collateral Vessels For Heart Damage

A., Marmor, E., Feldkamp, M. et al. 2002 . Aberrant G protein signaling in nervous system tumors. J Neurosurg 97 3 , 627-642. 76. Lau, N., Feldkamp, M., Roncari, L. et al. 2000 . Loss of NF1 causes activation of Ras MAPK and PI-3K Akt signaling in an NFl-associated astrocytoma. J Neuropathology Expt Neurology 59 9 , 759-767. 77. Ding, H., Roncari, L., Shannon, P. et al. 2001 . Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a...

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...

Conclusions

The role for chemotherapy in the treatment of pineal parenchymal tumors remains undefined, due to the low incidence of these neoplasms and the lack of clinical trial results. There is consensus that patients in whom a complete resection has been performed for a pineocytoma should not receive chemotherapy, and can be followed closely with serial MRI scans. Chemotherapy may be of benefit for these patients after they have developed locally recurrent tumor or disseminated disease. Patients with...

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...

References

Central Brain Tumor Registry of the United States www. cbtrus.org. 2. Lashford, L. S., Thiesse, P., Jouvet, T. et al. 2002 . Temozolo-mide in malignant gliomas of childhood a United Kingdom Children's Cancer Study Group and French Society for Pediatric Oncology Intergroup Study. J Clin Oncol 20, 4684-4691. 3. Grossman, S. A., and Batara, J. F. 2004 . Current management of glioblastoma multiforme. Semin Oncol 31, 635-644. 4. Kemper, E. M., Boogerd, W., Thuis, I. et al. 2004 . Modulation of...

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...

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...

Chemotherapy Of Pineal Parenchymal Tumors

The use of chemotherapy for the treatment of pineal region neoplasms has been applied mainly to CNS germ cell tumors, which is extensively reviewed in Chapter 33. The experience with pineal parenchymal tumors is more limited and mainly consists of small institutional series of patients 8,9, 15,37 . In the majority of cases, chemotherapy has been applied to patients with recurrent or progressive pineoblastoma, with less frequent application to those with recurrent pineocytoma. Objective...

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...

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...

Angiogenesis In Brain Tumor Models

Marked neovascularization is a hallmark of many neoplasms in the CNS. Vascular pathology is a key feature of glioblastoma multiforme characterized by hypervascularity, vascular permeability and hyper-coagulability. Vascular endothelial growth factor VEGF has been investigated as a potent mediator of brain tumor angiogenesis, vascular permeability, and glioma growth and is known to be upregulated in most cases of glioblastoma multiforme 89-101 . Microvessel density and VEGF levels have been...

Farnesylated Proteins other than p21Ras

The importance of farnesylation towards the post-translational maturation of p21-Ras has been discussed above. However, there are 200 other farnesylated human proteins, including several nuclear laminins and ocular lens proteins 80 . The best characterized non-p21-Ras-farnesylated protein is RhoB 81,82 , which can be processed by both farnesylation and geranyl-geranylation like the various p21-Ras sub-types discussed above. Similar to K-Ras and N-Ras, in the presence of FTIs, RhoB becomes...

Flavopiridol

Flavopiridol, a synthetic analog of a natural alkaloid, was shown to have potent CDK4-blocking activity 115 . Initial studies with this flavonoid demonstrated its ability to induce G1 S as well as G2 M cell cycle arrest due to loss of CDK1 and CDK2 activity 116-118 . Flavopiridol was shown to bind to the ATP-binding pocket of CDK2 and, thus, competes with ATP for binding 115 Fig. 9.7 . Unlike olomou-cine and roscovitine which show some CDK specificity, flavopiridol inhibits all CDKs as well as...

What Are Carrot Shaped Brain Tumors

Glial Cells The Brain

FIGURE 1.11 WHO grades II and III ependymoma. The typical low-grade tumor is densely cellular and composed of oval to carrot-shaped cells, with dense speckled nuclei and tapering eosinophilic cytoplasm 11A H amp E 200x . Note the ependymal perivascular psuedorosette in the center of the field. The anaplastic ependymoma is more pleomorphic and demonstrates mitotic activity 11B H amp E 400x . See Plate 1.11 in Color Plate Section. composed of oval to carrot-shaped cells, with a dense speckled...

Therapeutic Disruption Or Circumvention Of The

If the BBB is indeed an impediment to successful brain tumor treatment, it would make sense to try to temporarily ''open'' it, or circumvent it altogether. Rapoport and colleagues first described the effect of intra-arterial infusions of hypertonic solutions on the integrity of the BBB, and hypothesized about the potential therapeutic applications 30,44 . Clinically, BBB disruption, with an increase in the delivery of drugs and or macromolecules to the brain, has been most often produced by...