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Preclinical Experimental Therapeutics |
Department of Neurological Surgery, Brain Tumor Research Center (R.S., M.T.K., M.S.B., K.S.B.), and Division of Hematology-Oncology (C.O.N., J.W.P.), University of California, San Francisco, San Francisco, CA 94103; and Hermes Biosciences, Inc., South San Francisco, CA 94080 (D.C.D., D.B.K.); USA
2 Address correspondence to Krystof S. Bankiewicz, Department of Neurological Surgery, University of California at San Francisco, 1855 Folsom Street, Mission Center Building Room 226, San Francisco, CA 94103 (kbank{at}itsa.ucsf.edu).
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Abstract |
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= 1.5 days), whereas free topotecan was rapidly cleared (t = 0.1 days) after CED. The favorable pharmacokinetic profile of extended topotecan release for about seven days, along with biodistribution featuring perivascular accumulation of the nanoparticles, provided, in addition to the known topoisomerase I inhibition, an effective antiangiogenic therapy. In the rat intracranial U87MG tumor model, vascular targeting of Ls-TPT with CED was associated with reductions in laminin expression and vascular density compared to free topotecan or control treatments. A single CED treatment on day 7 showed that free topotecan conferred no survival benefit versus control. However, Ls-TPT produced a significant (P = 0.0002) survival benefit, with six of seven complete cures. Larger U87MG tumors, where CED of Ls-TPT on day 12 resulted in one of six cures, indicated the necessity to cover the entire tumor with the infused therapeutic agent. CED of Ls-TPT was also efficacious in the intracranial U251MG tumor model (P = 0.0005 versus control). We conclude that the combination of a novel nanoparticle Ls-TPT and CED administration was very effective in treating experimental brain tumors.
Key Words: antiangiogenesis • brain tumor • convection-enhanced delivery • liposome • topotecan
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Introduction |
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Topotecan is a water-soluble camptothecin analog that binds and inhibits topoisomerase I, leading to DNA damage in tumors (Kohn et al., 2000). Topotecan has shown cytotoxicity toward a variety of tumor types, including ovarian cancer, small-cell lung cancer, and gliomas (Friedman et al., 1994; Houghton et al., 1995; ten Bokkel Huinink et al., 1997, 2004). However, while significant activity has been noted in treating brain tumors (Rapisarda et al., 2004), its clinical use has been limited by its systemic toxicity (Lesimple et al., 2003; Pipas et al., 2005). Delivery via CED of free topotecan to brain tumors is currently under investigation as a means to avoid systemic toxicity (Kaiser et al., 2000).
To improve the systemic pharmacological profile of camptothecin drugs, drug delivery systems such as liposome encapsulation have been actively pursued. Topotecan transforms from an active lactone configuration to an inactive carboxylate configuration while in the circulation system, an equilibrium that is in turn affected by binding to plasma proteins (Burke and Gao, 1994; Chourpa et al., 1998; Mi et al., 1995). Encapsulation in acidic liposomes can help maintain topotecan in the active lactone form (Burke and Gao, 1994) and thus may help improve its activity in vivo.
Visualization of drug distribution during and after CED is crucial in a clinical setting, where the objective is to cover the tumor mass completely to maximize therapeutic effect. We have established a noninvasive method for detection of gadolinium-loaded liposomes in rodent brain tumors after CED that uses MRI (Mamot et al., 2004; Saito et al., 2004). These studies have led to development of a method for real-time monitoring of liposomal agents with gadolinium-loaded liposomes in primate brain (Krauze et al., 2005a; Saito et al., 2005), which can be used to optimize CED administration of these nanoparticle agents.
In this study, we report the efficacy of a novel, highly stable, nanoparticle-liposome-encapsulated topotecan delivered by CED to brain tumors. This locally infused liposomal topotecan (Ls-TPT) exerted strong antiangiogenic activity and demonstrated an excellent selective toxicity against human glioblastoma xenografts, significantly prolonging the survival of tumor-bearing rats.
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Materials and Methods |
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Topotecan-loaded liposomes were prepared with a modified, remote-loading, ion-gradient and intraliposomal drug-stabilization method. Briefly, after the lipids were dried in chloroform-methanol (9:1, v/v), they were dried by rotary evaporation and subsequently under vacuum for 2 h. The lipids were then resuspended in 1 ml of ethanol at 60°C. An aqueous solution of triethylammonium sucrose octasulfate (TEA8SOS, 0.65 M) was prepared by cation-exchange chromatography as previously described (Drummond et al., 2005) and was also heated to 60°C. The TEA8SOS solution was then injected rapidly into the ethanolic lipid solution to form liposomes. The liposomes were sized by extrusion through polycarbonate filters of average size 0.1 µm, which resulted in an average size of 105-122 nm. Unencapsulated TEA8SOS was removed by Sepharose CL-4B (GE Healthcare, Chalfont St. Giles, U.K.) size-exclusion chromatography, eluting with HEPES-buffered dextrose (5 mM HEPES and 5% dextrose, pH 6.5). Topotecan was added at a ratio of 350 g TPT/mol phospholipid, and loading was initiated by adjusting the pH to 6.5 and incubating the mixture for 30 min at 60°C, followed by quenching on ice for 15 min. Unencapsulated TPT was removed by Sephadex G-75 (GE Healthcare) gel filtration chromatography, eluting with HEPES-buffered saline (5 mM HEPES and 145 mM NaCl, pH 6.5); the drug concentration and phospholipid concentration of the purified solution were determined, spectrophotometrically at 375 nm after dissolution in acidic methanol and by a standard phosphate assay (Bartlett, 1959), respectively. The loading efficiency was always greater than 95% for the preparations used in these studies.
Cell Lines and Animals
Established human glioblastoma multiforme (GBM) cell lines U87MG and U251MG were obtained from the Brain Tumor Research Center Tissue Bank at the University of California, San Francisco. Cells were maintained as monolayers in a complete medium consisting of Eagle's minimal essential medium supplemented with 10% fetal calf serum, nonessential amino acids, 0.1 mg/ml of streptomycin sulfate, and 100 U/ml of penicillin G. Cells were cultured at 37°C in a humidified atmosphere consisting of 95% air and 5% CO2. Congenitally athymic, male, nude rats (rnu/rnu, homozygous) were purchased from the National Cancer Institute (Bethesda, Md.) and were housed under aseptic conditions, which included filtered air and sterilized food, water, bedding, and cages. Animals weighed approximately 250 g at the initiation of the studies. All protocols used in the animal studies were approved by the University of California, San Francisco, Institutional Animal Care and Use Committee.
Intracranial Tumor Implantation
Cells were harvested by trypsinization, washed once with Hanks' balanced salt solution without Ca2+ and Mg2+ (HBSS), and resuspended in HBSS for implantation. A cell suspension containing 5 x 105 cells/10 µl HBSS was used for implantation into the striatum of rat brains. Under deep isoflurane anesthesia, rats were placed in a small-animal stereotactic frame (David Kopf Instruments, Tujunga, Calif.). A sagittal incision was made through the skin to expose the cranium, and a small dental drill was used to make a burr hole in the skull 0.5 mm anterior and 3 mm lateral to the bregma. A 5-µl cell suspension was injected at a depth of 4.5 mm from the brain surface. After 2 min, another 5 µl was injected at a depth of 4 mm. After a final interval of 2 min, the needle was removed, and the wound was sutured.
Convection-Enhanced Delivery
A sagittal incision was made in the skin to expose the cranium, and with a small dental drill, a burr hole was made in the skull 0.5 mm anterior and 3 mm lateral to the bregma (for CED into tumor-bearing rats, the same burr hole made at the time of tumor implantation was used). Infusions were performed at a depth of 4.5 mm from the brain surface by using the CED method described in our previous studies (Mamot et al., 2004; Saito et al., 2004). Briefly, an infusion cannula connected to a Hamilton syringe (Hamilton, Reno, Nev.) was attached to a rate-controllable microinfusion pump (Bioanalytical Systems, Lafayette, Ind.). Slow-infusion CED was performed with an ascending schedule of infusion rates to achieve a total volume of 20 µl (0.2 µl/min for 15 min, 0.5 µl/min for 10 min, and 0.8 µl/min for 15 min). After infusion, the cannula was removed and the wound sutured.
Detection of Fluorescently Labeled Liposomes
Ten days after tumor implantation, four rats received CED of fluorescent liposomes labeled with DiIC18(3)-DS at a phospholipid concentration of 0.5 mM. All four rats were euthanized immediately after the infusion. The brains were harvested, freshly frozen in ice-cold isopentane, and cut into serial coronal sections (25 µm) with a cryostat. The fluorescent signal generated by DiIC18(3)-DS was visualized with a fluorescence microscope by excitation at 540/25 nm with a band-pass filter and with a long-pass filter at 565 nm for emission. A charge-coupled device camera with a fixed aperture was used to capture the image.
Evaluation of Toxicity
The CED of Ls-TPT (5 mg/ml [n = 4] or 0.5 mg/ml [n = 4]) was performed with normal Sprague-Dawley rats. Rats were observed for the development of any neurological symptoms and weight loss. On day 21 after drug administration, the brains were harvested and fixed with 10% formalin. Paraffin sections (5 µm) were cut and stained with hematoxylin and eosin (H&E).
Quantification of Topotecan After CED into Rat Brains
Rats were sacrificed at the prescribed times and the brains removed after perfusion with PBS. The brains were then frozen and kept at -80°C until analysis. The hemisphere receiving drug was homogenized by mortar and pestle under liquid nitrogen. Blank tissue homogenates were spiked with TPT to determine the efficiency of extraction. Homogenates of 50% tissue/water (100 µl) were extracted with 400 µl of methanol/0.1 M phosphoric acid (80:20) by vortexing for 10 s. The extraction mixture was kept at -80°C for 2 h and then centrifuged at 13,000 rpm for 15 min. The supernatant was transferred to a high-performance liquid chromatography (HPLC) autosampler vial that was maintained at 4°C. A 50-µl injection volume was used for each sample/standard. Separation was conducted on a C-18 reverse-phase silica column (Supelco, Bellefonte, Pa.; C-18 column, 250 mm x 4-mm i.d., particle size of 5 µm) with a C-18 guard column. A mobile phase, consisting of 3% triethylammonium acetate pH 5.5/acetonitrile (85:15), was used for isocratic elution, and TPT was detected by absorbance at 375 nm. TPT tissue spike extraction recovery was determined to be 101%.
Visualization of the Tumor Vasculature
To visualize blood vessels in tumors, immunohistochemical staining with laminin antibody (1:200 dilution; Sigma) was performed. Brains were fixed with 10% formalin, frozen with ice-cold isopentane, and cut into 40-µm sections. Floating sections were incubated with blocking solution (1% normal goat serum and 0.01% Triton X-100 in PBS) to reduce nonspecific background staining. Primary antibody was applied overnight at room temperature. On the following day, rhodamine-conjugated antirabbit serum (1:100 in blocking solution; Jackson ImmunoResearch Laboratories, West Grove, Pa.) was applied at room temperature for 1 h. After washing with PBS, sections were mounted onto microscope slides, covered with mounting medium (Gel/Mount; Biomeda, Foster City, Calif.), and sealed with coverslips. Cells were observed by phase contrast and fluorescence microscopy with a TRITC (tetramethylrhodamine isothiocyanate) filter (no. 31002; Chroma Technology Corp., Rockingham, Vt.), and a charge-coupled device camera with a fixed aperture was used to capture the images.
Western Blots
Tumors were harvested from the brain of rats infused by CED with fluorescent liposomes, free topotecan, or Ls-TPT. These tumors were homogenized, and protein was extracted in cell lysis buffer (Cell Signaling Technology, Beverly, Mass.). Equal amounts of protein were separated electrophoretically on a 7.5% sodium dodecyl sulfate-polyacrylamide gel and blotted onto polyvinylidene fluoride membrane (Bio-Rad, Hercules, Calif.). The polyvinylidene fluoride membrane was incubated in blocking buffer TBS (tris-buffered saline)/casein blocker; Bio-Rad), followed by anti-laminin ß-1 antibody (Santa Cruz Biotechnology, Santa Cruz, Calif.; 1:200, 4°C overnight), anti-phospho-Akt antibody (Cell Signaling Technology; 1:500, 4°C overnight), and anti-beta actin antibody (Sigma Bioscience; 1:1000, room temperature, 1 h). The blot was visualized with a colorimetric detection kit (Opti-4CN detection kit; Bio-Rad).
Antitumor Efficacy of Ls-TPT in U87 and U251 Xenografts
Thirty-three rats that received U87MG tumor cell implants were randomly divided into five groups: for the day 7 CED, the control group (n = 7), the free TPT group (n = 7), and the Ls-TPT group (n = 7), and for the day 12 CED, the control group (n = 6) and the liposomal TPT group (n = 6). Fourteen rats that received U251MG tumor cells implants were also randomly divided into two groups: the control group (n = 7) and the Ls-TPT group (n = 7).
Statistical Analysis
Results for the survival studies are expressed as a Kaplan-Meier plot. Survival between the treatment groups was compared with a log-rank test.
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Prolonged Retention of Topotecan by Liposomal Encapsulation
Either Ls-TPT or free topotecan was infused at 0.5 mg/ml into healthy Sprague-Dawley rat brains by CED to study drug clearance. Analysis of brain tissue revealed a dramatic improvement in brain retention of Ls-TPT as compared to that of free topotecan (Fig. 3). Tissue half-life of Ls-TPT was 1.5 days versus 0.1 days for free topotecan. The liposomal formulation extends the residence time of topotecan to the degree that it can be detected for as long as seven days after CED, whereas free TPT is completely cleared within one day. The longer residence time suggests that the Ls-TPT formulation remains stable during CED. After infusion, Ls-TPT presumably acts as a reservoir for the slow release of drug and thereby facilitates prolonged exposure of tumor tissue to the drug.
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Antiangiogenic Effects Detected After Local Application of Ls-TPT
To evaluate the antiangiogenic effect of this strategy, 18 rats were implanted intracranially with U87MG tumor cells. Ten days after tumor implantation, these rats were randomly divided into three groups (six rats per group): a control group that received no treatment, a free-topotecan group that received CED of free topotecan (0.5 mg/ml), and an Ls-TPT group that received CED of Ls-TPT (0.5 mg/ml). These rats were euthanized seven days after treatment, and the brains of three rats in each group were processed for immunohistochemical detection of blood vessels with antilaminin antibody (Fig. 4A). The tumor mass was removed from the brains of the other three rats in each group, and tumor protein was analyzed by Western blot to quantify blood vessels with antilaminin antibody. Immunohistochemical staining for laminin showed a marked decrease in blood vessels in the Ls-TPT group, whereas control and free-topotecan groups showed a similar high density (Fig. 4B). All three brains of rats treated with Ls-TPT and evaluated by Western blot demonstrated diminished expression of laminin in agreement with immunohistochemical data (Fig. 4B). Phosphorylation of Akt was also evaluated by Western blot, since topotecan has been demonstrated to inhibit the phosphorylation of Akt (Nakashio et al., 2000). Diminished levels of phosphorylated Akt were found in the Ls-TPT group, but not in the control or the free-topotecan groups (Fig. 4B).
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Prolonged Survival of U87MG or U251MG Intracranial Brain Tumor Xenograft Models with CED of Ls-TPT
A pilot study was initiated to evaluate the antitumor effect of Ls-TPT. Six athymic rats received U87MG tumor cell implantation and were randomly divided into a control group (n = 3) or Ls-TPT treatment group (n = 3). Ten days after tumor implantation, the latter group received CED of Ls-TPT (0.5 mg/ml, 20 µl), whereas the control group received fluorescent liposomal DiIC18. Nine days after infusion, rats were euthanized, and their brains were subjected to histological examination. Whereas all control rats developed large U87MG tumors (Fig. 5A), two rats from the treatment group revealed only tissue fibrosis (Fig. 5B, black arrowheads), and one rat from the same group revealed fibrosis tissue (Fig. 5C, black arrowhead) with a small, remaining viable tumor (Fig. 5C, white arrowhead). The brain tissue surrounding the fibrotic tissue was intact, which shows the excellent selective activity of this treatment against tumor tissue (Fig. 5B and C).
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Survival studies were performed using two well-established intracranial glioblastoma tumor xenograft models: U87MG and U251MG (Fig. 6). Twenty-one athymic rats received an implantation of U87MG tumor cells into their right striatum, and the rats were divided randomly into three groups. Seven days (almost one third of the life span of control animal) after tumor implantation, the first group (n = 7) received fluorescent liposomal DiIC18 as a control, the second group (n = 7) received CED of free topotecan (0.5 mg/ml, 20 µl), and the third group (n = 7) received CED of Ls-TPT (0.5 mg/ml topotecan, 20 µl) (Fig. 6A). Around days 17-26, all control rats and free-topotecan rats developed neurological symptoms due to large intracranial tumors confirmed as such by histology. Although free topotecan demonstrated no survival benefits at this low dose (P = 0.78), Ls-TPT at the same drug dose exerted a strong antitumor effect, and six out of seven rats survived until the study termination point of 100 days with no histological evidence of a tumor (P = 0.0002, Fig. 6A). Since the impact on survival of free topotecan is low at this dose (0.5 mg/ml, 20 µl), we focused on the efficacy of Ls-TPT in our following studies.
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To evaluate the treatment of larger tumors, the U87MG intracranial model was again developed in 12 rats. However, in this experiment, CED was performed 12 days after tumor implantation (Fig. 6B). Treatment groups were administered either a 20-µl infusion of control liposomes (n = 6) or 0.5 mg/ml of Ls-TPT (n = 6). Previous experiments showed that a U87 xenograft tumor at day 12 is not entirely covered by 20 µl liposomes (M.T.K., unpublished data). Although significant survival benefit was observed in this study (P = 0.0015, Fig. 6B), the response is clearly inferior to that in the treatment of smaller tumors, which are completely encompassed by the infused therapeutic agent. An intracranial tumor model with U251MG tumor cells was also developed with 12 athymic rats. Fourteen days (almost one third of the life span of this tumor model) after tumor implantation, six rats received fluorescent control liposomes, and the other six rats received Ls-TPT (0.5 mg/ml topotecan, 20 µl). Again, Ls-TPT showed significant survival benefit in the U251MG tumor model (P = 0.0005, Fig. 6C) demonstrating that the efficacy of Ls-TPT is not restricted to a single tumor model.
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Discussion |
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Continuous low-level chemotherapy, known as metronomic dosing, is an attractive strategy for targeting cancer blood vessels (Browder et al., 2000; Hanahan et al., 2000; Kerbel and Kamen, 2004). In contrast to conventional chemotherapeutic regimens that use maximum tolerated doses of cytotoxic agents, followed by periods of rest to enable normal tissue to recover, metronomic dosing delivers a lower, uninterrupted dose that continuously targets the genetically stable, newly developing endothelial cells. Many studies demonstrate improved efficacy by continuous low-dose scheduling compared to conventional dosing (Bocci et al., 2003; Klement et al., 2000, 2002; Man et al., 2002). The in vitro experiments of Bocci and colleagues (2002) demonstrated a difference between tumor cells and proliferating endothelial cells in sensitivity to various chemotherapeutic drugs, and they proved that continuous low-dose exposure to certain kinds of drugs predominantly suppresses the growth of endothelial cells (Bocci et al., 2002). Several groups also have reported that very low (e.g., nanomolar) concentrations of certain drugs such as paclitaxel (Belotti et al., 1996), topotecan, camptothecin (Clements et al., 1999; O'Leary et al., 1999), or vinblastine (Vacca et al., 1999) can significantly block the growth of endothelial cells, but not necessarily tumor cells in vitro. One significant advantage of stably encapsulated liposomal cytotoxic drugs over corresponding unencapsulated agents, when infused systemically, is extended drug half-life (Drummond et al., 1999). Similarly, prolongation of liposome drug half-life was observed in our study after CED to the CNS. Thus, we hypothesized that, after local delivery, liposomes slowly leak the encapsulated drug to the interstitium, enabling a continuous low dose of chemotherapy, which prolongs exposure of the targeted tissue to the drug.
We evaluated the effects of Ls-TPT against intracranial glioblastoma xenograft in the rat. The choice of drug was based on the fact that topotecan displays preferential antiangiogenic effects at low concentrations (Clements et al., 1999; O'Leary et al., 1999) and that systemic topotecan is now under clinical investigation for treating human, malignant gliomas (Gross et al., 2005; Lesimple et al., 2003). At doses not toxic to normal brain tissue, Ls-TPT exerted strong antiangiogenic activity in the U87MG intracranial xenograft model. Moreover, free topotecan at the same dose as Ls-TPT demonstrated no efficacy, which was likely due in part to the rapid clearance observed in our tissue-retention study. Thus, once dispensed locally, liposomes work as a drug source for effective continuous low-dose chemotherapy, slowly releasing the encapsulated drugs to surrounding tissues. This delay is also suggestive of a slow release of encapsulated compound from liposomes. Stable encapsulation of drugs is an important criterion for effective intravenous drug delivery via liposomes, as well (Drummond et al., 1999). We have recently developed a novel intraliposomal drug stabilization technology for preparing highly stable formulations of potent anticancer drugs (Drummond et al., 2005, and unpublished experiments). This stability appears to be at least partially responsible for the prolonged retention in brain tissue, as well.
The mechanism responsible for inhibition of angiogenesis by topotecan is not clearly understood. However, Nakashio et al. (2002) have reported that topotecan inhibits phosphorylation of Akt and that this may provide antiangiogenic activity. In our study, this apparent inhibition of Akt phosphorylation was observed to parallel the decrease in laminin expression. In addition, similar to results in other reports demonstrating the efficacy of antiangiogenic regimens, CED of Ls-TPT demonstrated an excellent selective toxicity against tumor tissues (Fig. 5). CED of Ls-TPT inhibited growth or completely eradicated orthotopic U87MG or U251MG xenografts, whereas free drug exerted almost no effect with the dose of 10 µg used in this study. We believe that the limited efficacy of Ls-TPT in day 12 treatment in the U87MG xenograft model (Fig. 6B) is caused by two problems: (1) incomplete tumor coverage by the therapeutic agent after CED and (2) inadequate release of TPT from liposomes at this late stage of tumor progression. The ability to image in real time the distribution of liposomes within the brain (Saito et al., 2004, 2005) provides a means for verifying optimal tumor coverage of liposomal therapeutics with a coinfused surrogate liposomal marker.
To expand our promising results into a clinical trial, several key points need to be discussed. To date, CED of chemotherapeutics is used in clinical trials only after surgical tumor resection to perfuse the rejection margins and therefore should prevent regrowth of malignancy. We believe also that very large inoperable brain tumors may be amenable to liposomal CED. Because the human CNS is large, this application would require implantation of several catheters into the targeted area to achieve complete coverage of malignant tissue. The slow release of Ls-TPT and the antiangiogenic effect of Ls-TPT in combination with CED have the potential to improve outcomes in brain tumor patients.
In conclusion, we have shown that Ls-TPT in combination with CED displayed excellent selective toxicity for tumor tissue relative to normal tissue, an important requirement when applying CED to clinical treatment of malignant brain tumors. In addition to the tumoricidal effects of topoisomerase I inhibition by TPT, the perivascular accumulation and the favorable pharmacokinetic profile of Ls-TPT provide an antiangiogenic effect. Because of its high selectivity and superior efficacy in the context of CED, Ls-TPT may be an excellent candidate for future clinical development.
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Footnotes |
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3 Abbreviations used are as follows: CED, convection-enhanced delivery; DiIC18, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindo-carbocyanine-perchlorate; GBM, glioblastoma multiforme; HBSS, Hanks' balanced salt solution; H&E, hematoxylin and eosin; HEPES, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; HPLC, high-performance liquid chromatography; Ls-TPT, liposomal topotecan; TEA8SOS, triethylammonium sucrose octasulfate.
Received for publication October 28, 2005. Accepted for publication January 6, 2006.
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References |
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Bartlett, G.R. (1959) Colorimetric assay methods for free and phosphorylated glyceric acids. J. Biol. Chem. 234, 469-471.
Belotti, D., Vergani, V., Drudis, T., Borsotti, P., Pitelli, M.R., Viale, G., Giavazzi, R., and Taraboletti, G. (1996) The microtubule-affecting drug paclitaxel has antiangiogenic activity. Clin. Cancer Res. 2, 1843-1849.[Abstract]
Bobo, R.H., Laske, D.W., Akbasak, A., Morrison, P.F., Dedrick, R.L., and Oldfield, E.H. (1994) Convection-enhanced delivery of macromolecules in the brain. Proc. Natl. Acad. Sci. USA 91, 2076-2080.
Bocci, G., Nicolaou, K.C., and Kerbel, R.S. (2002) Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs. Cancer Res. 62, 6938-6943.
Bocci, G., Francia, G., Man, S., Lawler, J., and Kerbel, R.S. (2003) Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc. Natl. Acad. Sci. USA 100, 12917-12922.
Browder, T., Butterfield, C.E., Kraling, B.M., Shi, B., Marshall, B., O'Reilly, M.S., and Folkman, J. (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 60, 1878-1886.
Burke, T.G., and Gao, X. (1994) Stabilization of topotecan in low pH liposomes composed of distearoylphosphatidylcholine. J. Pharm. Sci. 83, 967-969.[CrossRef][Medline]
Burke, T.G., and Mi, Z. (1994) The structural basis of camptothecin interactions with human serum albumin: Impact on drug stability. J. Med. Chem. 37, 40-46.[CrossRef][ISI][Medline]
Chourpa, I., Millot, J.M., Sockalingum, G.D., Riou, J.F., and Manfait, M. (1998) Kinetics of lactone hydrolysis in antitumor drugs of camptothecin series as studied by fluorescence spectroscopy. Biochim. Biophys. Acta 1379, 353-366.[Medline]
Clements, M.K., Jones, C.B., Cumming, M., and Daoud, S.S. (1999) Antiangiogenic potential of camptothecin and topotecan. Cancer Chemother. Pharmacol. 44, 411-416.[CrossRef][Medline]
Drummond, D.C., Meyer, O., Hong, K., Kirpotin, D.B., and Papahadjopoulos, D. (1999) Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmacol. Rev. 51, 691-743.
Drummond, D.C., Marx, C., Guo, Z., Scott, G., Noble, C., Wang, D., Pallavicini, M., Kirpotin, D.B., and Benz, C.C. (2005) Enhanced pharmacodynamic and antitumor properties of a histone deacetylase inhibitor encapsulated in liposomes or ErbB2-targeted immunoliposomes. Clin. Cancer Res. 11, 3392-3401.
Friedman, H.S., Houghton, P.J., Schold, S.C., Keir, S., and Bigner, D.D. (1994) Activity of 9-dimethylaminomethyl-10-hydroxycamptothecin against pediatric and adult central nervous system tumor xenografts. Cancer Chemother. Pharmacol. 34, 171-174.[ISI][Medline]
Groothuis, D.R. (2000) The blood-brain and blood-tumor barriers: A review of strategies for increasing drug delivery. Neuro-Oncology 2, 45-59.[Abstract]
Gross, M.W., Altscher, R., Brandtner, M., Haeusser-Mischlich, H., Chiricuta, I.C., Siegmann, A.D., and Engenhart-Cabillic, R. (2005) Openlabel simultaneous radio-chemotherapy of glioblastoma multiforme with topotecan in adults. Clin. Neurol. Neurosurg. 107, 207-213.[CrossRef][ISI][Medline]
Gupta, T., and Sarin, R. (2002) Poor-prognosis high-grade gliomas: Evolving an evidence-based standard of care. Lancet Oncol. 3, 557-564.[CrossRef][Medline]
Hanahan, D., Bergers, G., and Bergsland, E. (2000) Less is more, regularly: Metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J. Clin. Invest. 105, 1045-1047.[ISI][Medline]
Houghton, P.J., Cheshire, P.J., Hallman, J.D., 2nd, Lutz, L., Friedman, H.S., Danks, M.K., and Houghton, J.A. (1995) Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors. Cancer Chemother. Pharmacol. 36, 393-403.[ISI][Medline]
Kaiser, M.G., Parsa, A.T., Fine, R.L., Hall, J.S., Chakrabarti, I., and Bruce, J.N. (2000) Tissue distribution and antitumor activity of topotecan delivered by intracerebral clysis in a rat glioma model. Neurosurgery 47, 1391-1398.[ISI][Medline]
Kerbel, R.S., and Kamen, B.A. (2004) The anti-angiogenic basis of metronomic chemotherapy. Nat. Rev. Cancer 4, 423-436.[CrossRef][ISI][Medline]
Klement, G., Baruchel, S., Rak, J., Man, S., Clark, K., Hicklin, D.J., Bohlen, P., and Kerbel R.S. (2000) Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J. Clin. Invest. 105, R15-R24.
Klement, G., Huang, P., Mayer, B., Green, S.K., Man, S., Bohlen, P., Hicklin, D., and Kerbel, R.S. (2002) Differences in therapeutic indexes of combination metronomic chemotherapy and an anti-VEGFR-2 antibody in multidrug-resistant human breast cancer xenografts. Clin. Cancer Res. 8, 221-232.
Kohn, K.W., Shao, R.G., and Pommier, Y. (2000) How do drug-induced topoisomerase I-DNA lesions signal to the molecular interaction network that regulates cell cycle checkpoints, DNA replication, and DNA repair? Cell Biochem. Biophys. 33, 175-180.[CrossRef][Medline]
Krauze, M.T., McKnight, T.R., Yamashita, Y., Bringas, J., Noble, C.O., Saito, R., Geletneky, K., Forsayeth, J., Berger, M.S., Jackson, P., Park, J.W., and Bankiewicz, K.S. (2005a) Real-time visualization and characterization of liposomal delivery into the monkey brain by magnetic resonance imaging. Brain Res. Brain Res. Protoc. 16, 20-26.[CrossRef][Medline]
Krauze, M.T., Saito, R., Noble, C., Bringas, J., Forsayeth, J., McKnight, T.R., Park, J., and Bankiewicz, K.S. (2005b) Effects of the perivascular space on convection-enhanced delivery of liposomes in primate putamen. Exp. Neurol. 196, 104-111.[CrossRef][ISI][Medline]
Kunwar, S. (2003) Convection enhanced delivery of IL13-PE38QQR for treatment of recurrent malignant glioma: Presentation of interim findings from ongoing phase 1 studies. Acta Neurochir. Suppl. 88, 105-111.[Medline]
Lesimple, T., Hassel, M.B., Gedouin, D., Seigneuret, E., Carsin, B., Hamlat, A., Riffaud, L., Simon, H., Malhaire, J.P, and Guegan, Y. (2003) Phase I study of topotecan in combination with concurrent radiotherapy in adults with glioblastoma. J. Neurooncol. 65, 141-148.[Medline]
Mamot, C., Nguyen, J.B., Pourdehnad, M., Hadaczek, P., Saito, R., Bringas, J.R., Drummond, D.C., Hong, K., Kirpotin, D.B., McKnight, T., Berger, M.S., Park, J.W., and Bankiewicz, K.S. (2004) Extensive distribution of liposomes in rodent brains and brain tumors following convection-enhanced delivery. J. Neurooncol. 68, 1-9.[Medline]
Man, S., Bocci, G., Francia, G., Green, S.K., Jothy, S., Hanahan, D., Bohlen, P., Hicklin, D.J., Bergers, G., and Kerbel, R.S. (2002) Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water. Cancer Res. 62, 2731-2735.
Mi, Z., Malak, H., and Burke, T.G. (1995) Reduced albumin binding promotes the stability and activity of topotecan in human blood. Biochemistry 34, 13722-13728.[CrossRef][Medline]
Nakashio, A., Fujita, N., Rokudai, S., Sato, S., and Tsuruo, T. (2000) Prevention of phosphatidylinositol 3'-kinase-Akt survival signaling pathway during topotecan-induced apoptosis. Cancer Res. 60, 5303-5309.
Nakashio, A., Fujita, N., and Tsuruo, T. (2002) Topotecan inhibits VEGF- and bFGF-induced vascular endothelial cell migration via downregulation of the PI3K-Akt signaling pathway. Int. J. Cancer 98, 36-41.[CrossRef][Medline]
O'Leary, J.J., Shapiro, R.L., Ren, C.J., Chuang, N., Cohen, H.W., and Potmesil, M. (1999) Antiangiogenic effects of camptothecin analogues 9-amino-20(S)-camptothecin, topotecan, and CPT-11 studied in the mouse cornea model. Clin. Cancer Res. 5, 181-187.
Pipas, J.M., Meyer, L.P., Rhodes, C.H., Cromwell, L.D., McDonnell, C.E., Kingman, L.S., Rigas, J.R., and Fadul, C.E. (2005) A phase II trial of paclitaxel and topotecan with filgrastim in patients with recurrent or refractory glioblastoma multiforme or anaplastic astrocytoma. J. Neurooncol. 71, 301-305.[CrossRef][Medline]
Rapisarda, A., Zalek, J., Hollingshead, M., Braunschweig, T., Uranchimeg, B., Bonomi, C.A., Borgel, S.D., Carter, J.P., Hewitt, S.M., Shoemaker, R.H., and Melillo, G. (2004) Schedule-dependent inhibition of hypoxia-inducible factor-1
protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts. Cancer Res. 64, 6845-6848.
Saito, R., Bringas, J.R., McKnight, T.R., Wendland, M.F., Mamot, C., Drummond, D.C., Kirpotin, D.B., Park, J.W., Berger, M.S., and Bankiewicz, K.S. (2004) Distribution of liposomes into brain and rat brain tumor models by convection-enhanced delivery monitored with magnetic resonance imaging. Cancer Res. 64, 2572-2579.
Saito, R., Krauze, M.T., Bringas, J.R., Noble, C., McKnight, T.R., Jackson, P, Wendland, M.F., Mamot, C., Drummond, D.C., Kirpotin, D.B., Hong, K., Berger, M.S., Park, J.W., and Bankiewicz, K.S. (2005) Gadolinium-loaded liposomes allow for real-time magnetic resonance imaging of convection-enhanced delivery in the primate brain. Exp. Neurol. 196, 381-389.[CrossRef][ISI][Medline]
Saito, R., Krauze, M.T., Noble, C.O., Tamas, M., Drummond, D.C., Kirpotin, D.B., Berger, M.S., Park, J.W., and Bankiewicz, K.S. (2006) Tissue affinity of the infusate affects the distribution volume during convection-enhanced delivery into rodent brains: Implications for local drug delivery. J. Neurosci. Methods [epub ahead of print], Feb. 9.
Stewart, L.A. (2002) Chemotherapy in adult high-grade glioma: A systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359, 1011-1018.[CrossRef][ISI][Medline]
ten Bokkel Huinink, W., Gore, M., Carmichael, J., Gordon, A., Malfetano, J., Hudson, I., Broom, C., Scarabelli, C., Davidson, N., Spanczynski, M., Bolis, G., Malmstrom, H., Coleman, R., Fields, S.C., and Heron, J.F. (1997) Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J. Clin. Oncol. 15, 2183-2193.
ten Bokkel Huinink, W., Lane, S.R., Ross, G.A., and the International Topotecan Study Group (2004) Long-term survival in a phase III, randomised study of topotecan versus paclitaxel in advanced epithelial ovarian carcinoma. Ann. Oncol. 15, 100-103.
Vacca, A., Ribatti, D., Presta, M., Minischetti, M., Iurlaro, M., Ria, R., Albini, A., Bussolino, F., and Dammacco, F. (1999) Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma. Blood 93, 3064-3073.
Vogelbaum, M.A. (2005) Convection enhanced delivery for the treatment of malignant gliomas: Symposium review. J. Neurooncol. 73, 57-69.[CrossRef][Medline]
Walter, K.A., Tamargo, R.J., Olivi, A., Burger, P.C., and Brem, H. (1995) Intratumoral chemotherapy. Neurosurgery 37, 1128-1145.[Medline]
Weller, R.O., Kida, S., and Zhang, E.T. (1992) Pathways of fluid drainage from the brain—morphological aspects and immunological significance in rat and man. Brain Pathol. 2, 277-284.[ISI][Medline]
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