Treatment Of Human Brain Tumors Research Articles

Electroporation-Based Therapy for Brain Tumors: A Review.

Electroporation-based therapy (EBT), as a high-voltage-pulse technology has been prevalent with favorable clinical outcomes in the treatment of various solid tumors. This review paper aims to promote the clinical translation of EBT for brain tumors. First, we briefly introduced the mechanism of pore formation in a cell membrane activated by external electric fields using a single cell model. Then, we summarized and discussed the current in vitro and in vivo preclinical studies, in terms of (1) the safety and effectiveness of EBT for brain tumors in animal models, and (2) the blood-brain barrier (BBB) disruption induced by EBT. Two therapeutic effects could be achieved in EBT for brain tumors simultaneously, i.e., the tumor ablation induced by irreversible electroporation (IRE) and transient BBB disruption induced by reversible electroporation (RE). The BBB disruption could potentially improve the uptake of antitumor drugs thereby enhancing brain tumor treatment. The challenges that hinder the application of EBT in the treatment of human brain tumors are discussed in the review paper as well.

Poly(ethylene glycol)-Poly(beta-amino ester)-Based Nanoparticles for Suicide Gene Therapy Enhance Brain Penetration and Extend Survival in a Preclinical Human Glioblastoma Orthotopic Xenograft Model.

Glioblastoma (GBM) is the most devastating brain cancer, and cures remain elusive with currently available neurosurgical, pharmacological, and radiation approaches. While retrovirus- and adenovirus-mediated suicide gene therapy using DNA encoding herpes simplex virus-thymidine kinase (HSV-tk) and prodrug ganciclovir has been suggested as a promising strategy, a nonviral approach for treatment in an orthotopic human primary brain tumor model has not previously been demonstrated. Delivery challenges include nanoparticle penetration through brain tumors, efficient cancer cell uptake, endosomal escape to the cytosol, and biodegradability. To meet these challenges, we synthesized poly(ethylene glycol)-modified poly(beta-amino ester) (PEG-PBAE) polymers to improve extracellular delivery and coencapsulated plasmid DNA with end-modified poly(beta-amino ester) (ePBAE) polymers to improve intracellular delivery as well. We created and evaluated a library of PEG-PBAE/ePBAE nanoparticles (NPs) for effective gene therapy against two independent primary human stem-like brain tumor initiating cells, a putative target to prevent GBM recurrence. The optimally engineered PEG-PBAE/ePBAE NP formulation demonstrated 54 and 82% transfection efficacies in GBM1A and BTIC375 cells respectively, in comparison to 37 and 66% for optimized PBAE NPs without PEG. The leading PEG-PBAE NP formulation also maintained sub-250 nm particle size up to 5 h, while PBAE NPs without PEG showed aggregation over time to micrometer-sized complexes. The comparative advantage demonstrated in vitro successfully translated into improved in vivo diffusion, with a higher amount of PEG-PBAE NPs penetrating to a distance of 2 mm from the injection site. A significant increase in median survival from 53.5 to 67 days by PEG-PBAE/pHSV-tk NP and systemic ganciclovir treatment compared to a control group in orthotopic murine model of human glioblastoma demonstrates the potential of PEG-PBAE-based NPs as an effective gene therapy platform for the treatment of human brain tumors.

Nanomedicine-Based Combination Anti-Cancer Therapy between Nucleic Acids and Anti-Cancer Nano Drugs in Covalent Nano Drugs Delivery Systems for Selective Imaging and Treatment of Human Brain Tumors Using Hyaluronic Acid, Alguronic Acid and Sodium Hyaluronate as Anti-Cancer Nano Drugs and Nucleic Acids Delivery under Synchrotron Radiation

Nanomedicine-based combination anti-cancer therapy between nucleic acids and anti-cancer Nano drugs in covalent Nano drugs delivery systems for selective imaging and treatment of human brain tumors using hyaluronic acid, alguronic acid and sodium hyaluronate (Figures 1 and 2) as anti-cancer Nano drugs and nucleic acids delivery under synchrotron radiation has been explored as an alternative approach to the synthesis of electronically and optically active polymers with several advantages1-33. Horseradish Peroxidase (HRP) catalyzes the decomposition of Hydrogen peroxide (H2O2) at the expense of aromatic proton donors. Horseradish Peroxidase (HRP) is a Fe containing porphyrin-type structure. In previous works, we synthesized hyaluronic acid, alguronic acid and sodium hyaluronate, enzymatically1-33. The results of enzymatic polymerization were different from chemical and electrochemical polymerization of hyaluronic acid, alguronic acid and sodium hyaluronate that reported previously1-33. In this editorial, we reported the enzymatic copolymerization of aniline and hyaluronic acid, alguronic acid and sodium hyaluronate with Horseradish Peroxidase (HRP) in the presence of Sulfonated Polystyrene (SPS) as a template.

Therapeutic Potential of Curcumin for the Treatment of Brain Tumors.

Brain malignancies currently carry a poor prognosis despite the current multimodal standard of care that includes surgical resection and adjuvant chemotherapy and radiation. As new therapies are desperately needed, naturally occurring chemical compounds have been studied for their potential chemotherapeutic benefits and low toxicity profile. Curcumin, found in the rhizome of turmeric, has extensive therapeutic promise via its antioxidant, anti-inflammatory, and antiproliferative properties. Preclinical in vitro and in vivo data have shown it to be an effective treatment for brain tumors including glioblastoma multiforme. These effects are potentiated by curcumin's ability to induce G2/M cell cycle arrest, activation of apoptotic pathways, induction of autophagy, disruption of molecular signaling, inhibition of invasion, and metastasis and by increasing the efficacy of existing chemotherapeutics. Further, clinical data suggest that it has low toxicity in humans even at large doses. Curcumin is a promising nutraceutical compound that should be evaluated in clinical trials for the treatment of human brain tumors.

Platinum (IV) coiled coil nanotubes selectively kill human glioblastoma cells

Malignant glioma are often fatal and pose a significant therapeutic challenge. Here we have employed α-helical right handed coiled coils (RHCC) which self-assemble into tetrameric nanotubes that stably associate with platinum (Pt) (IV) compound. This Pt(IV)-RHCC complex showed superior in vitro and in vivo toxicity in human malignant glioma cells at up to 5 fold lower platinum concentrations when compared to free Pt(IV). Pt(IV)-RHCC nanotubes activated multiple cell death pathways in GB cells without affecting astrocytes in vitro or causing damage to normal mouse brain. This Pt(IV)-RHCC nanotubes may serve as a promising new therapeutic tool for low dose Pt(IV) prodrug application for highly efficient and selective treatment of human brain tumors. From the Clinical EditorThe prognosis of malignant glioma remains poor despite medical advances. Platinum, one of the chemotherapeutic agents used, has significant systemic side effects. In this article, the authors employed α-helical right handed coiled coil (RHCC) protein nanotubes as a carrier for cisplatin. It was shown that the new compound achieved higher tumor kill rate but lower toxicity to normal cells and thus may hold promise to be a highly efficient treatment for the future.

Over expression of PPP2R2C inhibits human glioma cells growth through the suppression of mTOR pathway

PPP2R2C encodes a gamma isoform of the subunit B55 subfamily, which is a regulatory subunit of Protein phosphatase type 2A (PP2A). Our study shows that PPP2R2C is downregulated in glioma cells and human brain cancer patient samples. Overexpression of PPP2R2C inhibited cancer cell proliferation both in vitro and in vivo through the suppression of the activity of S6K in the mTOR pathway. Moreover, exogenous expression of PPP2R2C promoted the formation of a complex with the PP2A-C subunit to further enhance the binding of PP2A-C with S6K. Our results suggest that PPP2R2C is a potential tumor suppressor gene in human brain cancers. This study will provide novel insight into the development of therapeutic strategies in the treatment of human brain tumors.

Abstract 582: Targeting the blood-brain barrier with a non-canonical iron-mimicry mechanism: A translational approach for the detection and treatment of human brain tumors

Abstract Treatment of central nervous system (CNS) diseases is limited by the blood-brain barrier (BBB), a selective vascular interface restricting passage of most molecules from blood into brain. Here we used the in vivo phage display technology to isolate peptide-targeted phage particles that can cross the BBB under normal and pathological conditions. We show that a non-canonical association of (i) transferrin, (ii) an iron-mimic ligand motif, and (iii) transferrin receptor mediates binding and transport of phage particles into the normal mouse brain through an allosteric mechanism. We also show that, in an orthotopic human glioma model, a combination of transferrin receptor overexpression plus extended vascular permeability and ligand retention results in remarkable brain tumor targeting. Such unique attributes enable molecular imaging and targeted therapy of intracranial tumors in a clinic-ready setting. Finally, we expand our data by analyzing a large panel of primary CNS tumors through comprehensive tissue microarrays. Together, our approach and results provide a translational avenue for the detection and treatment of brain tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 582.

Abstract C233: BAL27862: A unique microtubule-targeted agent with a potential for the treatment of human brain tumors

Abstract Background: BAL27862 is a synthetic small molecule, potently inducing apoptosis in cancer cells through tubulin depolymerization characterized by a unique microtubule phenotype. BAL27862 has demonstrated a broad in vitro anti-proliferative activity against a range of human tumor histotypes (low nM IC50s). Significant antitumor responses occur in animal models of human cancer after oral or intravenous (i.v.) administration, including tumors refractory to conventional treatments. The purpose of this study was to investigate the tissue distribution of BAL27862 in tumor-bearing mice. Tumor and brain penetration, together with anti-proliferative activity in glioblastoma (GBM) cell lines, is described. Materials and Methods: Anti-proliferative activity and induction of tumor cell death in vitro were analyzed using the YO-PRO® assay (48h incubation). CD1 nu/nu female mice were implanted with human colon carcinoma SW480 cells. For pharmacokinetic studies, tumor-bearing (approx. 150 mm3) mice were administered i.v. with either 2 mg/kg 14C-BAL27862 (n=6, single dose) or 8 mg/kg cold BAL27862 (n=33, once-weekly during 4 weeks). Animals were culled at serial time points. Radioactivity was measured in slices, with Bio-Imaging Analyzer read-outs of the exposed phosphor imaging plates quantified with Aida software. Cold BAL27862 was determined in plasma, brain and tumors using a specific LC-MS/MS method after sample homogenization and protein precipitation. Results: BAL27862 elicited a potent anti-proliferative activity in 6 GBM cell lines (IC50 range: 10–20nM), which was independent of PTEN status. Strikingly, at optimal concentrations, a dramatic loss of cell viability was observed (% cell death at 50nM BAL27862: >15% in 5 lines, >30% in 2 lines), demonstrating that BAL27862 potently drives GBM cells into a cell death program..In mice, after i.v. administration of 14C-BAL27862, radioactivity was distributed to all organs: notably brain and tumor. A delayed peak was observed in slowly perfused organs such as skin, tumor and fat-tissue. There was no tissue-specific retention of radioactivity, as halflives were comparable between tissues and blood. 48h after administration, radioactivity was almost undetectable in most tissues. Following administration of 8 mg/kg i.v. cold BAL27862 to mice, the excellent brain and tumor penetration was confirmed. Specifically, similar levels of BAL27862 were found in brain and plasma (Cmax of 6.86 µg/g and 7.34 µg/mL, respectively). The ratio tumor/plasma was also around 1. There was no brain or tumor accumulation over time, as concentrations paralleled those in plasma. Conclusions: BAL27862 is efficiently distributed to tissues and tumor in a mouse model of human cancer. Significant brain penetration, coupled with cytotoxic activity in GBM tumor cell lines, would support further evaluation of BAL27862 for the treatment of human brain cancers. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C233.

Isolation of drug delivery from drug effect: Problems of optimizing drug delivery parameters1

A recurring question in the treatment of malignant brain tumors has been whether treatment failure is due to inadequate delivery or ineffective drugs. To isolate these issues, we tested a paradigm in which the "therapeutic" agent was a toxin about which there could be no question of efficacy, provided it was delivered in adequate amounts; we used 10% formalin. We infused 10% formalin into 5- to 8-mm subcutaneous RG-2 and D54-MG gliomas at increasing rates until we achieved 100% tumor cell kill. In RG-2 gliomas, infusions of 10 microl/h x 7 days, and 2, 4, 6, and 8 microl/min x 2 h failed to kill tumors, although growth was delayed, while infusion rates of 12 microl/min x 60 min and 48 microl/min x 15 min produced 100% tumor kill. In D54-MG tumors, infusions of 4, 8, and 24 microl/min produced 100% tumor kill. 14C-Formalin autoradiographs showed a heterogeneous distribution after infusions of 2 microl/min x 2 h, whereas infusions of 48 microl/min x 15 min showed a homogeneous distribution within the tumor, but more than 95% of tissue radioactivity was found in tissue surrounding tumor. Drug delivery remains a major issue in brain tumor treatment: Distribution inhomogeneity, rapid efflux, and consequent treatment failures are likely due to high interstitial fluid pressure. Because the infusion rates being used in the treatment of human brain tumors are low and the tumors are larger, treatment failures can be expected on the basis of inadequate drug delivery alone, regardless of the effectiveness of the drug.

Genetic strategies for brain tumor therapy

Gene therapy is a potentially useful approach in the treatment of human brain tumors, which are notoriously refractory to conventional approaches. Most human clinical trials to date have been unsuccessful in terms of improving patient outcome. Recent improvements in viral vectors, the development of stem cell technology, and increased understanding of the mechanism of action of therapeutic transgenes provide hope that the next generation of gene therapeutics may show increased efficacy in treatment of this devastating disease.

Dexamethasone inhibits the HSV-tk/ ganciclovir bystander effect in malignant glioma cells

BackgroundHSV-tk/ ganciclovir (GCV) gene therapy has been extensively studied in the setting of brain tumors and largely relies on the bystander effect. Large studies have however failed to demonstrate any significant benefit of this strategy in the treatment of human brain tumors. Since dexamethasone is a frequently used symptomatic treatment for malignant gliomas, its interaction with the bystander effect and the overall efficacy of HSV-TK gene therapy ought to be assessed.MethodsStable clones of TK-expressing U87, C6 and LN18 cells were generated and their bystander effect on wild type cells was assessed. The effects of dexamethasone on cell proliferation and sensitivity to ganciclovir were assessed with a thymidine incorporation assay and a MTT test. Gap junction mediated intercellular communication was assessed with microinjections and FACS analysis of calcein transfer. The effect of dexamethasone treatment on the sensitivity of TK-expressing to FAS-dependent apoptosis in the presence or absence of ganciclovir was assessed with an MTT test. Western blot was used to evidence the effect of dexamethasone on the expression of Cx43, CD95, CIAP2 and BclXL.ResultsDexamethasone significantly reduced the bystander effect in TK-expressing C6, LN18 and U87 cells. This inhibition results from a reduction of the gap junction mediated intercellular communication of these cells (GJIC), from an inhibition of their growth and thymidine incorporation and from a modulation of the apoptotic cascade.ConclusionThe overall efficacy of HSV-TK gene therapy is adversely affected by dexamethasone co-treatment in vitro. Future HSV-tk/ GCV gene therapy clinical protocols for gliomas should address this interference of corticosteroid treatment.

Percival Bailey and the classification of brain tumors

Throughout his illustrious career, Percival Bailey made numerous contributions to the fields of neurology, neuroanatomy, psychiatry, neuropathology, and, of course, neurosurgery. His expertise, his curiosity about the nervous system, and his desire to examine it from all angles were unique. With the exception of Harvey Cushing, Dr. Bailey made some of the greatest contributions in the area of neuro-oncology at the turn of the last century. In this essay the authors summarize the key episodes of Bailey's life and discuss his impact on the classification and treatment of human brain tumors.

Gene therapy using an adenovirus vector for apoptosis-related genes is a highly effective therapeutic modality for killing glioma cells.

Preclinical studies in animal models and human clinical trials have evaluated the safety and efficacy of adenoviral vectors for cancer gene therapy. These studies have indicated that gene delivery via adenoviral vectors, including p53 gene therapy, represents a promising therapeutic modality for many types of human cancers. This review focuses on novel strategies to induce apoptosis in glioma cells by transduction with adenoviral vectors carrying a variety of apoptosis-related genes, including Fas ligand, Fas, FADD, caspase-8, p53, p33ING1, p73alpha, Bax, Apaf-1, caspase-9, IkappaBdN, caspase-3, Bcl-2, and Bcl-X(L). We conclude that adenoviral vector-mediated delivery of apoptosis-related genes other than p53 is a potentially useful gene therapy approach toward the treatment of human brain tumors.

Structure-activity relationships of alkylphosphocholine derivatives: antineoplastic action on brain tumor cell lines in vitro.

Erucylphosphocholine (ErPC) is a promising candidate for the treatment of human brain tumors. The aim of the present study was to investigate whether structural modifications of ErPC would improve its antineoplastic activity in vitro. The novel alkylphosphocholine (APC) derivatives docosenyl-( cis-10,11)-phosphocholine, tricosenyl-( cis-12,13)-phosphocholine, heneicosenyl-( cis-12,13)-phosphocholine and erucyl- N, N, N-trimethylpropanolaminophosphate all reduced cell growth and viability of rat and human astrocytoma/glioblastoma (AC/GBM) cell lines (C6, T98G, U87MG, A172) and had improved antineoplastic activity when compared to the prototypical APC hexadecylphosphocholine (HePC). However, the four cell lines differed in their sensitivity to the APC derivatives. A172 cells were most sensitive to their cytostatic action and T98G cells to their cytotoxic action. The LC(50) values for T98G cells after a 72-h exposure to the novel derivatives varied between 25 and 54 microM compared to 45+/-8.1 microM for ErPC. Complete killing of T98G cells was obtained with all derivatives at 90 microM. Structural modifications of the chain length of the alcohol moiety as well as changing the position of the double bond within the alkyl chain improved cytotoxicity of the APC in C6 and A172 cells and to a lesser extent in T98G cells, whereas U87MG cells showed almost similar sensitivities to the novel drugs and ErPC. Increasing the distance between the phosphorus and nitrogen atoms within the polar phosphocholine group did not alter antineoplastic activity but modified physicochemical characteristics, e.g. increased the solubility in water. In a similar manner to ErPC, all derivatives induced growth arrest in the G(2)/M phase of the cell cycle and apoptotic cell death. Importantly, none of the derivatives showed hemolytic activity. As there was no clear superiority of any of the novel derivatives, ErPC remains the leading APC derivative for future clinical trials in brain tumor chemotherapy.

Acetaminophen selectively reduces glioma cell growth and increases radiosensitivity in culture.

Glioblastoma multiforme (GBM) is a highly lethal brain cancer. Using cultures of rodent and human malignant glioma cell lines, we demonstrated that millimolar concentrations of acetylsalicylate, acetaminophen, and ibuprofen all significantly reduce cell numbers after several days of culture. However, their mechanisms of action may vary, as demonstrated by (1) differences in the morphological changes produced by these compounds; (2) varied responses to these drugs with respect to toxicity kinetics; and (3) respective rates of cell proliferation, DNA synthesis, and mitotic index. We studied the effects of acetaminophen on relative cell number further. Evidence is presented that acetaminophen induced cell death by an apoptotic mechanism after a brief burst of mitosis in which cell numbers increased transiently, followed by a reduction in cell number and an increase in DNA fragmentation, as evidenced by terminal deoxytransferase-mediated dUTP-biotin nick end labeling (TUNEL) analysis. Using cultures of adult human brain and embryonic rat brain, we demonstrated that glioma cells were several-fold more sensitive to acetaminophen than normal brain cells in culture. Finally, subtoxic doses of acetaminophen increased the sensitivity of the human glioma cells in culture to ionizing radiation. Taken together, these results suggest that acetaminophen may prove to be a useful therapeutic agent in the treatment of human brain tumors.

Photodynamic therapy of U87 human glioma in nude rat using liposome-delivered photofrin.

Liposomes as photosensitizer carriers may enhance the photodynamic effect on tumors. To test this hypothesis, we treated U87 human glioma in rat brain with photodynamic therapy (PDT) using Photofrin encapsulated in a liposome carrier or Photofrin in dextrose. Nontumored brain was also treated and Photofrin content ratios were measured in tumor and nontumored brain. PDT using the liposome encapsulated photosensitizer significantly increased tumor destruction compared to PDT with Photofrin in dextrose (P = 0.007), whereas no difference in tissue damage was detected in nontumored brain with or without liposome carrier. Photofrin uptake was also significantly elevated in the liposome vehicle group compared to the dextrose (P < 0.05) group. Our data suggest that Photofrin encapsulated in a liposome may enhance the PDT treatment of human brain tumors.

A novel multiply-mutated HSV-1 strain for the treatment of human brain tumors.

A promising approach for the therapeutic treatment of brain tumors utilizes replication-competent, neuroattenuated herpes simplex virus-1 (HSV-1) mutants. This approach requires mutation of HSV-1 to eliminate killing of normal, nondividing cells of the brain (e.g., neurons). We have generated a HSV-1 double-mutant, designated 3616UB, by interrupting the uracil DNA glycosylase (UNG) gene in a previously studied ICP34.5 mutant, R3616. The HSV-1-encoded UNG gene is required for efficient HSV-1 replication in nondividing cells, but is dispensable for replication in rapidly dividing cells. The specific function of the HSV-1 ICP34.5 gene is not completely clear, but it is thought to be necessary for viral replication in cells of the nervous system, because, when mutated, the resultant viral strains are fully neuroattenuated. Strain 3616UB did not replicate in primary neuronal cultures in vitro or in mouse brain, but efficiently killed six of six human tumor cell lines within 6 days in vitro and successfully infected and replicated within brain tumor xenografts. The potential safety of 3616UB for human use is enhanced by an unexpected hypersensitivity to the antiherpetic drug ganciclovir. These data suggest that 3616UB may be effective for the treatment of human brain tumors. Intratumoral injection of 3616UB into human medulloblastoma or angiosarcoma xenografts established in severe combined immunodeficient (SCID) mice produced significant growth arrest and some tumor regressions. Strain 3616UB was as effective as R3616 in this therapy study and did not cause any obvious distress in the treated animals. Together, the data show that 3616UB is a very safe alternative to other HSV-1 mutants because the presence of two mutations reduces the possibility of recombinational events in situ that could lead to the generation of virulent viral progeny during 3616UB therapy.

Cisplatin and radiation in the treatment of tumors of the central nervous system: pharmacological considerations and results of early studies

Purpose : To review the human central nervous system pharmacology of cisplatin, factors that affect cisplatin uptake in tumors, and use alone and with radiation for the treatment of primary brain tumors. Methods and Materials : The authors review their own prior published and unpublished experience and data published by other groups on the above issues. Results : Cisplatin is one of the most active chemotherapy drugs available for the treatment of solid tumors. It is synergistic with several other agents, including radiation. While it attains only low concentrations in the normal central nervous system, concentrations and plasma-tissue transfer constants for human intracerebral tumors are comparable to those in extracerebral tumors. Tumor type appears to be a more important determinant of platinum concentration than is tumor location, and gliomas do achieve lower concentrations than do other intracerebral or excracerebral tumors. Several other factors have also been identified that correlate with concentrations of cisplatin achieved in human tumors. While cisplatin alone and in combination with other drugs does have some degree of efficacy against primary brain tumors, combining it with cranial irradiation has generally not resulted in any substantial improvement in outcome to date, although some individual studies have been somewhat encouraging. New approaches are currently under investigation. Conclusion : Human pharmacology studies provide a rationale for use of cisplatin in the treatment of human brain tumors, and human and in vitro studies suggest some manipulations that might potentially further augment tumor platinum concentrations. While clinical studies suggest that cisplatin combinations may be of some value vs. human primary brain tumors and brain metastases, and while in vitro studies suggest that cisplatin potentiates radiation efficacy, no combination of cisplatin plus radiation yet tested has appeared to be superior to radiation alone.

Photoactivated Photofrin II: astrocytic swelling precedes endothelial injury in rat brain.

Light activation of circulating hematoporphyrin derivatives has been used in the treatment of selected brain tumors. The effects of this photodynamic therapy on the non-neoplastic, adjacent brain tissue are incompletely characterized. We studied in adult Fisher rats the time-dependent (1 hour to 7 days) effects of photoactivated Photofrin II. Our protocol was comparable to that used in the treatment of human brain tumors. Structural and functional changes spread from the treatment surface and from the center to the periphery to involve the entire cerebral cortex exposed under a 5 mm craniectomy. The sequential changes spreading from the surface to the deepest cortical layer involve first astrocytes (1 hour), then endothelial cells and, ultimately, neurons. Thrombi were first noted in the microvasculature after 18 hours and coagulation necrosis of the entire area at risk occurred only after 48 hours. The results suggest that the photosensitizing agent crosses the intact blood-brain barrier and enters the astrocytic compartment where it becomes cytotoxic upon light activation. A comparison between the focal brain lesions of photodynamic therapy and those induced by middle cerebral artery occlusion suggests that cell damage evolves along different paths in these two forms of brain injury.

Liposome-Entrapped Human Interferon-β

Human interferon-β (HuIFN-β) entrapped in liposomes composed of egg phosphatidylcholine, cholesterol, and sulfatide was examined for its antitumor activity against brain tumor cells in vitro and its pharmacokinetics in vivo. HuIFN-β did not lose its biological activity during the preparation of the liposomes. The liposomes entrapped 7-14% of the HuIFN-β used, suggesting that the majority of HuIFN-β was embedded in the liposomal membranes. Cytotoxicity of the liposome-entrapped HuIFN-β against human tumor cells was comparable with that of free HuIFN-β. Intravenous injection of the liposome-entrapped HuIFN-β resulted in higher interferon levels in the blood, liver, spleen, brain, and transplant of human brain tumor, compared with free HuIFN-β. These data show that the liposome-entrapped HuIFN-β should be useful in the treatment of human brain tumors.